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  • 1. Cerny, Robert
    et al.
    Ericsson, Rolf
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Meulemans, Daniel
    Bronner-Fraser, Marianne
    Epperlein, Hans-Henning
    Mandibular Arch Morphogenesis and the Origin of Jaws: What Does "Maxillary" and "Mandibulary" Really MeanManuscript (Other academic)
  • 2.
    Ericsson, Rolf
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    A Comparative Study of Head Development in Mexican Axolotl and Australian Lungfish: Cell Migration, Cell Fate and Morphogenesis2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of the vertebrate head is a complex process involving interactions between a multitude of cell types and tissues. This thesis describes the development of the cranial neural crest and of the visceral arch muscles in the head of two species. One, the Mexican axolotl (Ambystoma mexicanum), is a basal tetrapod, whereas the other, the Australian lungfish (Neoceratodus forsteri), belongs to the Dipnoi, the extant sister group of the Tetrapoda.

    The migration of neural crest cells, which form most of the bones and connective tissues in the head, and the morphogenesis of the jaw, was determined in the Mexican axolotl. It was shown that both the upper and lower jaws form from ventral condensations of neural crest cells in the mandibular arch. The dorsal condensation, earlier considered to give rise to the upper jaw, was shown to form the trabecula cranii.

    The normal spatio-temporal development of visceral arch muscles was investigated in both the Mexican axolotl and the Australian lungfish. In axolotl, the muscles tended to start forming almost simultaneously in all visceral arches at their future origins and extend towards their future insertions at the onset of muscle fibre formation. In lungfish, fibres formed simultaneously throughout most of each muscle anlage in the first and second visceral arch, but were delayed in the branchial arches. The anlagen were first observed at their future insertion, from which they developed towards future origins.

    To test the ability of neural crest cells to pattern the visceral arch muscles, migrating crest cells were extirpated from axolotl embryos, which resulted in a wide range of muscle malformations. In most cases, the muscles appeared in the right position but were small and extended in abnormal directions. This shows that neural crest cells are responsible not for the position of the muscles but for their correct anatomical pattern. Fate mapping showed that connective tissue surrounding myofibers is, at least partly, neural crest derived.

    In conclusion, the work presented in this thesis shows that although early development may map out the patterns of later development, the differences between axolotl and lungfish head development are not seen until during morphogenesis. Further investigation of morphogenesis is needed to explain the great variation of head morphology seen in vertebrates today.

    List of papers
    1. Patterns of Spatial and Temporal Visceral Arch Muscle Development in the Mexican axolotl (Ambystoma mexicanum)
    Open this publication in new window or tab >>Patterns of Spatial and Temporal Visceral Arch Muscle Development in the Mexican axolotl (Ambystoma mexicanum)
    2004 (English)In: Journal of morphology (1931. Print), ISSN 0362-2525, E-ISSN 1097-4687, Vol. 261, no 2, p. 131-140Article in journal (Refereed) Published
    Abstract [en]

    Vertebrate head development is a classical topic that has received renewed attention during the last decade. Most reports use one of a few model organisms (chicken, mouse, zebrafish) and have focused on molecular mechanisms and the role of the neural crest, while cranial muscle development has received less attention. Here we describe cranial muscle differentiation and morphogenesis in the Mexican axolotl, Ambystoma mexicanum. To determine the onset of differentiation we use antibodies against desmin and optical sectioning using confocal laser scanning microscopy on whole-mount immunostained embryos. This technique makes it possible to document the cranial muscle in three dimensions while keeping the specimens intact. Desmin expression starts almost simultaneously in the first, second, and third visceral arch muscles (as in other amphibians studied). Muscle anlagen divide up early into the different elements which constitute the larval cranial musculature. We extend and refine earlier findings, e.g., by documenting a clear division between interhyoideus and interhyoideus posterior. The timing of cranial muscle differentiation differs among vertebrate groups, but seems to be constant within each group. This study provides a morphological foundation for further studies of muscle cell fate and early differentiation.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90468 (URN)10.1002/jmor.10151 (DOI)15216519 (PubMedID)
    Available from: 2003-05-15 Created: 2003-05-15 Last updated: 2017-12-14Bibliographically approved
    2. The Role of Cranial Neural Crest Cells in Visceral Arch Muscle Positioning and Patterning in the Mexican axolotl, Ambystoma mexicanum
    Open this publication in new window or tab >>The Role of Cranial Neural Crest Cells in Visceral Arch Muscle Positioning and Patterning in the Mexican axolotl, Ambystoma mexicanum
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90469 (URN)
    Available from: 2003-05-15 Created: 2003-05-15 Last updated: 2010-01-13Bibliographically approved
    3. Mandibular Arch Morphogenesis and the Origin of Jaws: What Does "Maxillary" and "Mandibulary" Really Mean
    Open this publication in new window or tab >>Mandibular Arch Morphogenesis and the Origin of Jaws: What Does "Maxillary" and "Mandibulary" Really Mean
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90470 (URN)
    Available from: 2003-05-15 Created: 2003-05-15 Last updated: 2010-01-13Bibliographically approved
    4. Visceral Arch Muscle Development in the Australian lungfish (Neoceratodus forsteri)
    Open this publication in new window or tab >>Visceral Arch Muscle Development in the Australian lungfish (Neoceratodus forsteri)
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90471 (URN)
    Available from: 2003-05-15 Created: 2003-05-15 Last updated: 2010-01-13Bibliographically approved
  • 3.
    Ericsson, Rolf
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Cerny, Robert
    Falck, Pierre
    Olsson, Lennart
    The Role of Cranial Neural Crest Cells in Visceral Arch Muscle Positioning and Patterning in the Mexican axolotl, Ambystoma mexicanumManuscript (Other academic)
  • 4.
    Ericsson, Rolf
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Joss, Jean
    Olsson, Lennart
    Visceral Arch Muscle Development in the Australian lungfish (Neoceratodus forsteri)Manuscript (Other academic)
  • 5.
    Ericsson, Rolf
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Olsson, Lennart
    Patterns of Spatial and Temporal Visceral Arch Muscle Development in the Mexican axolotl (Ambystoma mexicanum)2004In: Journal of morphology (1931. Print), ISSN 0362-2525, E-ISSN 1097-4687, Vol. 261, no 2, p. 131-140Article in journal (Refereed)
    Abstract [en]

    Vertebrate head development is a classical topic that has received renewed attention during the last decade. Most reports use one of a few model organisms (chicken, mouse, zebrafish) and have focused on molecular mechanisms and the role of the neural crest, while cranial muscle development has received less attention. Here we describe cranial muscle differentiation and morphogenesis in the Mexican axolotl, Ambystoma mexicanum. To determine the onset of differentiation we use antibodies against desmin and optical sectioning using confocal laser scanning microscopy on whole-mount immunostained embryos. This technique makes it possible to document the cranial muscle in three dimensions while keeping the specimens intact. Desmin expression starts almost simultaneously in the first, second, and third visceral arch muscles (as in other amphibians studied). Muscle anlagen divide up early into the different elements which constitute the larval cranial musculature. We extend and refine earlier findings, e.g., by documenting a clear division between interhyoideus and interhyoideus posterior. The timing of cranial muscle differentiation differs among vertebrate groups, but seems to be constant within each group. This study provides a morphological foundation for further studies of muscle cell fate and early differentiation.

  • 6.
    Ginjala, Vasudeva
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Transcriptional Silencing in the Imprinted Igf2-H19 Loci: The Mystique of Epigenetics2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genomic imprinting marks a subset of autosomal loci expressed in parent of origin-dependent monoallelic expression in a non-Mendelian fashion. To restore totipotency and to reset the imprint according to the sex of the individual, the mark must be erased during germline development. The imprinted Igf2-H19 loci located distally on chromosome 7 in mouse and 11p15.5 in human, share common regulatory elements that regulate differential expression. Where the H19 is silenced when paternally inherited, the Igf2 is silenced when maternally inherited.

    The differentially methylated 5'-flank of H19 gene, termed imprinting control region (ICR), shown to display a unique chromatin organisation harbours hypersensitive sites in linker regions flanked by positioned nucleosomes on the maternal allele. This unique chromatin conformation functions as a methylation-sensitive and unidirectional chromatin insulator, which later was found to depend on the chromatin insulator protein CTCF.

    The H19 ICR exhibits default-silencing functions in promoter-proximal positions. The maximal distance between the H19 ICR and the promoter of the reporter gene required for this effect was 1.2 ± 0.3kb which can be compared to the 1.9 kb distance between the endogenous H19 ICR and H19 promoter. Results suggest that the H19 ICR adopts a chromatin conformation that must be separated by a minimal distance from pivotal cis-regulatory elements to avoid adverse effects on neighbouring promoters.

    Poly(ADP-ribosy)lation represents a novel post-translational epigenetic mark that segregates with exclusively the maternal derived H19 ICR and associated with factors that interact with the CTCF target sites. CTCF is itself poly(ADP-ribosy)lated and the poly(ADP-ribose) polymerase inhibitor 3-aminobenzamide relieves the insulator function of the H19 ICR.

    Designed zinc finger proteins were applied to examine if epigenetic marks provided an obstacle for targeted activation and silencing. The zinc finger protein ZFP809 with activator/repressor domain able to efficiently activate/silence the IGF2 target. Murine hybrid cell lines of human chromosome 11, demonstrated that the ZFP809 overcame the epigenetic marks that repressed maternal IGF2 and paternal H19 allele, respectively. Results suggested that imprinted genes are not normally exposed to strong cis-regulatory elements and that the designed ZFPs can be exploited to develop a therapeutic method for rectifying epigenetic lesions.

  • 7.
    Ginjala, Vasudeva
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Holmgren, Claes
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Kanduri, Chandrasekhar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Pant, Vinod
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Lobanenkov, Victor
    Franklin, Gary
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ohlsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Multiple cis elements within the Igf2/H19 insulator domain organize a distance-dependent silencer: A cautionary note2002In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 8, p. 5707-5710Article in journal (Refereed)
  • 8.
    Hedborg, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular tools.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Wassberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Maxwell, Patrick H
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Hero, Barbara
    Berthold, Frank
    Schilling, Freimut
    Harms, Dieter
    Sandstedt, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Franklin, Gary
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Evidence for hypoxia-induced neuronal-to-chromaffin metaplasia in neuroblastoma2003In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 17, no 6, p. 598-609Article in journal (Refereed)
    Abstract [en]

    We present evidence that in neuroblastoma, a pediatric malignancy of embryonal sympathetic origin, hypoxia, underlies a phenotypic switch from a primitive neuronal to a chromaffin cell type. This conclusion is based on morphological and molecular data on 116 clinical tumors and is supported by data on the phenotypic effects of hypoxia on neuroblastoma cell lines when studied in monolayer culture and as tumor xenografts. In the clinical material, extensive chromaffin features were seen in regions of chronic tumor hypoxia. This was the exclusive form of intra-tumoral maturation of stroma-poor tumors and was also seen in stroma-rich tumors, either exclusively or in combination with ganglion-like cells. In neuroblastoma cell lines, hypoxia induced changes in gene expression associated with the chromaffin features observed in vivo. We therefore propose tumor hypoxia as a major cue determining phenotype in sympathetic tumors of neuroblastic origin. Because it appears to be reversible upon reoxygenation in monolayer culture, we suggest the term metaplasia for the phenomenon.

  • 9.
    Holmgren, Claes
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Epigenetic Regulation of the H19 Chromatin Insulator in Development and Disease2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The coordinated regulation of gene expression must be tightly controlled for normal development to occur. In mammals, this issue is further complicated by the requirement of both the maternal and paternal genomes for normal development, reflecting the fact that a subset of genes are monoallelically expressed depending on parental inheritance, a phenomenon known as genomic imprinting.

    The imprinted H19 and Igf2 genes are often considered as paradigms of genomic imprinting, since their monoallelic expression patterns are coordinated via a short stretch of sequence upstream of H19, known as the imprinting control region (ICR). This region is differentially methylated, with specific CpG methylation on the paternal allele. It is shown here that the ICR harbours several maternal-specific hypersensitive sites, located in linker regions between positioned nucleosomes. Furthermore, this region functions as an orientation-dependent insulator, that binds the chromatin insulator factor CTCF. The hypothesis that the methylation status of the ICR dictates the activity of the Igf2 gene 90 kb further upstream was confirmed by the demonstration that the insulator function is lost when the ICR is CpG methylated.

    The ICR has previously been shown to act as a silencer when positioned in a promotor-proximal position. The cause of this silencing was shown to be distance-dependent, suggesting that the silencing features of the ICR depend on a chromatin conformation that renders adjacent sequences inaccessible to the RNA polymerase. These data issue a cautionary note with respect to the interpretation of silencer functions.

    In several forms of cancer, the normally silent maternal IGF2 gene is expressed, possibly as a result of loss of insulator function at the ICR. The utilisation of CTCF target-sites was analysed in different tumours, and was shown to be highly variable. Methylation analysis showed that potential loss of insulator function and gain of methylation at the maternal ICR did not always correlate with biallelic expression of IGF2. Further investigations uncovered a novel mechanism, in which the activation of the IGF2 promoter was independent of insulator function in some cancers.

    This thesis shows that the regulation of the imprinted state of Igf2 depends on the formation of an epigenetically regulated chromatin insulator, and that the loss of IGF2 imprinting in human cancer can be attributed to several mechanisms, including a novel mechanism that neutralises chromatin insulator function.

    List of papers
    1. The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication
    Open this publication in new window or tab >>The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication
    Show others...
    2000 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 10, no 8, p. 449-457Article in journal (Refereed) Published
    Keywords
    Alleles, Animals, Blotting; Southern, Cell Line, Chromatin/*chemistry, Enhancer Elements (Genetics), Female, Fetus, Humans, Insulin-Like Growth Factor II/*genetics, Male, Mice, Muscle Proteins/*genetics/metabolism, Plasmids, Polymerase Chain Reaction, Promoter Regions (Genetics), Protein Conformation, RNA; Untranslated, Terminal Repeat Sequences, Transformation; Genetic
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-24765 (URN)10.1016/S0960-9822(00)00442-5 (DOI)10801414 (PubMedID)
    Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2017-12-07Bibliographically approved
    2. CpG methylation regulates the Igf2/H19 insulator
    Open this publication in new window or tab >>CpG methylation regulates the Igf2/H19 insulator
    Show others...
    2001 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 11, no 14, p. 1128-1130Article in journal (Refereed) Published
    Abstract [en]

    The differentially methylated 5'-flank of the mouse H19 gene unidirectionally regulates the communication between enhancer elements and gene promoters and presumably represses maternal Igf2 expression in vivo [1-6]. The specific activation of the paternally inherited Igf2 allele has been proposed to involve methylation-mediated inactivation of the H19 insulator function during male germline development [1-4, 6]. Here, we addressed the role of methylation by inserting a methylated fragment of the H19-imprinting control region (ICR) into a nonmethylated episomal H19 minigene construct, followed by the transfection of ligation mixture into Hep3B cells. Individual clones were expanded and analyzed for genotype, methylation status, chromatin conformation, and insulator function. The results show that the methylated status of the H19 ICR could be propagated for several passages without spreading into the episomal vector. Moreover, the nuclease hypersensitive sites, which are typical for the maternally inherited H19 ICR allele [1], were absent on the methylated ICR, underscoring the suggestion that the methylation mark dictates parent of origin-specific chromatin conformations [1] that involve CTCF [2]. Finally, the insulator function was strongly attenuated in stably maintained episomes. Collectively, these results provide the first experimental support that the H19 insulator function is regulated by CpG methylation.

    Keywords
    Alleles, Animals, Cell Line, CpG Islands, DNA Methylation, Female, Genomic Imprinting, Male, Mice, Plasmids/genetics, RNA; Untranslated/*genetics
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90356 (URN)10.1016/S0960-9822(01)00314-1 (DOI)11509237 (PubMedID)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2017-12-14Bibliographically approved
    3. Multiple cis elements within the Igf2/H19 insulator domain organize a distance-dependent silencer: A cautionary note
    Open this publication in new window or tab >>Multiple cis elements within the Igf2/H19 insulator domain organize a distance-dependent silencer: A cautionary note
    Show others...
    2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 8, p. 5707-5710Article in journal (Refereed) Published
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-90357 (URN)10.1074/jbc.C100552200 (DOI)11777900 (PubMedID)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2017-12-14Bibliographically approved
    4. The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells: A novel mechanism of loss of IGF2 imprinting.
    Open this publication in new window or tab >>The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells: A novel mechanism of loss of IGF2 imprinting.
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90358 (URN)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2010-01-13Bibliographically approved
  • 10.
    Holmgren, Claes
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Kanduri, Chandra
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Dell, Ghislaine
    Ward, Andrew
    Mukhopadhya, Ritu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Lobanenkov, Victor
    Ohlsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    CpG methylation regulates the Igf2/H19 insulator2001In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 11, no 14, p. 1128-1130Article in journal (Refereed)
    Abstract [en]

    The differentially methylated 5'-flank of the mouse H19 gene unidirectionally regulates the communication between enhancer elements and gene promoters and presumably represses maternal Igf2 expression in vivo [1-6]. The specific activation of the paternally inherited Igf2 allele has been proposed to involve methylation-mediated inactivation of the H19 insulator function during male germline development [1-4, 6]. Here, we addressed the role of methylation by inserting a methylated fragment of the H19-imprinting control region (ICR) into a nonmethylated episomal H19 minigene construct, followed by the transfection of ligation mixture into Hep3B cells. Individual clones were expanded and analyzed for genotype, methylation status, chromatin conformation, and insulator function. The results show that the methylated status of the H19 ICR could be propagated for several passages without spreading into the episomal vector. Moreover, the nuclease hypersensitive sites, which are typical for the maternally inherited H19 ICR allele [1], were absent on the methylated ICR, underscoring the suggestion that the methylation mark dictates parent of origin-specific chromatin conformations [1] that involve CTCF [2]. Finally, the insulator function was strongly attenuated in stably maintained episomes. Collectively, these results provide the first experimental support that the H19 insulator function is regulated by CpG methylation.

  • 11.
    Holmgren, Claes
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Pant, Vinod
    Kanduri, Chandra
    Mariano, Piero
    Lai, Yu-peng
    Kanduri, Meena
    Öberg, Fredrik
    Papadogiannakis, Nikos
    Lobanenkov, Victor
    Pfeifer, Susan
    The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells: A novel mechanism of loss of IGF2 imprinting.Manuscript (Other academic)
  • 12. Holmgren, Claes
    et al.
    Pant, Vinod
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Kanduri, Chandrasekhar
    Mariano, Piero
    Lai, Yupeng
    Kanduri, Meena
    Öberg, Fredrick
    Papadogiannakis, N
    Lobanenkov, Victor
    Pfeifer, Susan
    Ohlsson, Rolf
    The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells : A novel mechanism of loss of IGF2 ImprintingManuscript (Other academic)
  • 13.
    Jiang, Lin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Carlström, Eva Lindholm
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Haloperidol changes mRNA expression of a QKI splice variant in human astrocytoma cells.2009In: BMC pharmacology, ISSN 1471-2210, Vol. 9, p. 6-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The quaking homolog, KH domain RNA binding (mouse) (QKI) is a candidate gene for schizophrenia. Disturbed QKI mRNA expression is observed in the prefrontal cortex of patients, and some of these changes correlate to treatment with antipsychotic drugs.To test if low doses of antipsychotic drugs can modify QKI mRNA expression, human astrocytoma (U343) and oligodendroglioma (HOG) cell lines were treated with five different antipsychotic drugs including Haloperidol, Aripiprazole, Clozapine, Olanzapine and Risperidone. Messenger RNA expression levels of splice variants QKI-5, QKI-6 and QKI-7 were measured by Real-Time PCR. RESULTS: Haloperidol treatment (0.2 microM) doubled QKI-7 mRNA levels in U343 cells after 6 hours (p-value < 0.02). The effect was dose dependent, and cells treated with ten times higher concentration (2 microM) responded with a five-fold and three-fold increase in QKI-7, 6 and 24 hours after treatment, respectively (p-values < 0.0001). CONCLUSION: The results in U343 cells suggest that QKI-7 mRNA expression in human astrocytes is induced by Haloperidol, at concentrations similar to plasma levels relevant to clinical treatment of schizophrenia. The molecular mechanism of action of antipsychotic drugs after binding to receptors is not well known. We hypothesize that QKI regulation is involved in this mechanism.

  • 14. Kanduri, C
    et al.
    Fitzpatrick, G
    Mukhopadhyay, R
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Kanduri, M
    Lobanenkov, V
    Ohlsson, R
    A differentially methylated imprinting control region within the Kcnq1 locus harbors a methylation-sensitive chromatin insulator.2002In: JBC, Vol. 277, p. 18106-18110Article in journal (Refereed)
  • 15.
    Kanduri, Chandra
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Holmgren, Claes
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Pilartz, Marcel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Franklin, Gary
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Liu, Liang
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ginjala, Vasudeva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Mattsson, Ragnar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ohlsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication2000In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 10, no 8, p. 449-457Article in journal (Refereed)
  • 16. Kanduri, Chandrasekhar
    et al.
    Fitzpatrick, Galina
    Mukhopadhyay, Rituparna
    Kanduri, Meena
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Lobanenkov, Victor
    Higgins, Michael
    Ohlsson, Rolf
    A differentially methylated imprinting control region within the Kcnq1 Locus harbors a methylation-sensitive chromatin insulator2002In: The Journal of biological chemistry, Vol. 277, no 20, p. 18106 - 18110Article in journal (Refereed)
  • 17. Kanduri, Chandrasekhar
    et al.
    Pant, Vinod
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Loukinov, Dmitri
    Pugacheva, Elena
    qi, Chen-Fen
    Wolffe, Alan
    Ohlsson, Rolf
    Lobanenkov, Victor
    Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin specific and methylation-sensitive2000In: Current Biology, ISSN 0960-9822, Vol. 10, no 14, p. 853-856Article in journal (Refereed)
  • 18.
    Kanduri, Meena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    The Functional Significance and Chromatin Organisation of the Imprinting Control Regions of the H19 and Kcnq1 Genes2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Genomic imprinting is a phenomenon through which a subset of genes are epigenetically marked during gemtogenisis. This mark is maintained in the soma to often manifest parent of origin-specific monoalleleic expresson patterns. Genetics evidence suggests that gene expression patterns in mprinted genes, which are frequently organised in clusters, are regulated by the imprinting control regions (ICR). This thesis is mainly focused on the mechanisms through which the ICRs control the imprinting in the cluster, containing the Kcnq1, Igf2 and H19 genes, located at the distal end of mouse chromosome 7.

    The H19 ICR, located in the 5' flank of the H19 gene represses paternal H19 and maternal Igf2 expression, respectively, but has no effect on Kcnq1 expression, which is controlled by another ICR located at the intron 10 of the Kcnq1 gene. This thesis demonstrates that the maternal H19 ICR allele contains several DNase I hypersensitive sites, which map to target sites for the chromatin insulator protein CTCF at the linker regions between the positioned nucleosomes. The thesis demonstrates that the H19 ICR acts as a unidirectional insulator and that this property invovles three nucleosome positioning sites facilitating interaction between the H19 ICR and CTCF. The Kcnq1 ICR function is much more complex, since it horbours both lineage-specific silencing functions and a methylation sensitive unidirectional chromatin insulator function. Importantly, the thesis demonstrates that the Kcnq1 ICR spreads DNA methylation into flanking region only when it is itself unmethylated. Both the methylation spreading and silencing functions map to the same regions.

    In conclusion, the thesis has unraveled and unrivalled complexity of the epigenetic control and function of short strtches of sequences. The epigenetic status of these cis elements conspires to control long-range silencing and insulation. The manner these imprinting control regions can cause havoc in expresson domains in human diseases is hence emerging.

    List of papers
    1. The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication
    Open this publication in new window or tab >>The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication
    Show others...
    2000 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 10, no 8, p. 449-457Article in journal (Refereed) Published
    Keywords
    Alleles, Animals, Blotting; Southern, Cell Line, Chromatin/*chemistry, Enhancer Elements (Genetics), Female, Fetus, Humans, Insulin-Like Growth Factor II/*genetics, Male, Mice, Muscle Proteins/*genetics/metabolism, Plasmids, Polymerase Chain Reaction, Promoter Regions (Genetics), Protein Conformation, RNA; Untranslated, Terminal Repeat Sequences, Transformation; Genetic
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-24765 (URN)10.1016/S0960-9822(00)00442-5 (DOI)10801414 (PubMedID)
    Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2017-12-07Bibliographically approved
    2. Mutiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 impriting control region
    Open this publication in new window or tab >>Mutiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 impriting control region
    Show others...
    2002 In: Molecular and Cellular Biology, Vol. 22, no 10, p. 3339 - 3344Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91380 (URN)
    Available from: 2004-02-20 Created: 2004-02-20Bibliographically approved
    3. A differentially methylated imprinting control region within the Kcnq1 Locus harbors a methylation-sensitive chromatin insulator
    Open this publication in new window or tab >>A differentially methylated imprinting control region within the Kcnq1 Locus harbors a methylation-sensitive chromatin insulator
    Show others...
    2002 In: The Journal of biological chemistry, Vol. 277, no 20, p. 18106 - 18110Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91381 (URN)
    Available from: 2004-02-20 Created: 2004-02-20Bibliographically approved
    4. Bidirectional silencing and DNA methylation-sensitive methylation-spreading properties of the Kcnq1 imprinting control region map to the same regions
    Open this publication in new window or tab >>Bidirectional silencing and DNA methylation-sensitive methylation-spreading properties of the Kcnq1 imprinting control region map to the same regions
    Show others...
    2003 In: The journal of biological chemistry, Vol. 278, no 11, p. 9514 - 9519Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91382 (URN)
    Available from: 2004-02-20 Created: 2004-02-20Bibliographically approved
  • 19.
    Kanduri, Meena
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Kanduri, Chandrasekhar
    Mariano, Piero
    Vostrov, Alexander
    Quitschke, Wolfgang
    Lobanenkov, Victor
    Ohlsson, Rolf
    Mutiple nucleosome positioning sites regulate the CTCF-mediated insulator function of the H19 impriting control region2002In: Molecular and Cellular Biology, Vol. 22, no 10, p. 3339 - 3344Article in journal (Refereed)
  • 20. Kemkemer, Claus
    et al.
    Kohn, Matthias
    Kehrer-Sawatzki, Hildegard
    Fundele, Reinald H
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Hameister, Horst
    Enrichment of brain-related genes on the mammalian X chromosome is ancient and predates the divergence of synapsid and sauropsid lineages2009In: Chromosome Research, ISSN 0967-3849, E-ISSN 1573-6849, Vol. 17, no 6, p. 811-820Article in journal (Refereed)
    Abstract [en]

    Previous studies have revealed an enrichment of reproduction- and brain-related genes on the human X chromosome. In the present study, we investigated the evolutionary history that underlies this functional specialization. To do so, we analyzed the orthologous building blocks of the mammalian X chromosome in the chicken genome. We used Affymetrix chicken genome microarrays to determine tissue-selective gene expression in several tissues of the chicken, including testis and brain. Subsequently, chromosomal distribution of genes with tissue-selective expression was determined. These analyzes provided several new findings. Firstly, they showed that chicken chromosomes orthologous to the mammalian X chromosome exhibited an increased concentration of genes expressed selectively in brain. More specifically, the highest concentration of brain-selectively expressed genes was found on chicken chromosome GGA12, which shows orthology to the X chromosomal regions with the highest enrichment of non-syndromic X-linked mental retardation (MRX) genes. Secondly, and in contrast to the first finding, no enrichment of testis-selective genes could be detected on these chicken chromosomes. These findings indicate that the accumulation of brain-related genes on the prospective mammalian X chromosome antedates the divergence of sauropsid and synapsid lineages 315 million years ago, whereas the accumulation of testis-related genes on the mammalian X chromosome is more recent and due to adaptational changes.

  • 21.
    Lindeberg, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Mattsson, Ragnar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Ebendal, Ted
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Timing the doxycycline yields different patterns of genomic recombination in brain neurons with a new inducible Cre transgene2002In: Journal of Neuroscience Research, ISSN 0360-4012, E-ISSN 1097-4547, Vol. 68, no 2, p. 248-253Article in journal (Refereed)
    Abstract [en]

    We have developed a transgenic mouse expressing the Cre recombinase under control of a tetracycline-responsive promoter. Using a CamKIIalpha-driven tTA transgenic strain and a lacZ reporter mouse, we obtained the expected neuronal pattern of recombination in the olfactory lobe, cortex, striatum, hippocampus and Purkinje cells. Moreover, recombination can be completely abolished by feeding the mice doxycycline in their drinking water. We also show that it is possible to get a different pattern of recombination by changing the timing of the doxycycline-mediated shutdown of Cre expression. By starting the doxycycline treatment at birth, we restrict recombination to striatum only. This approach should be applicable to other inducible transgenic strains, thus increasing the number of available tissue-specific patterns for conditional knockouts. Also, our tetO-Cre transgene can be combined with any of the increasing number of tetracycline transactivator transgenic strains to direct specifically inducible genomic recombination to several areas of the brain.

  • 22.
    Liu, Liang
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Epigenetic Control of Mammalian Development: Studies on an imprinting control region2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A subset of autosomal genes is preferentially or exclusively expressed from one of the parental alleles. This phenomenon, termed genomic imprinting, is highlighted by the neighboring Igf2 and H19 genes, which are monoallelically expressed on opposite parental chromosomes. These features are governed by a 2.2 kb differentially methylated domain, hereafter termed imprinting control region (ICR) in the 5'-flank of the H19 gene. It was shown that the H19 ICR displays unique chromatin conformation features with nuclease hypersensitive sites in linker elements flanked by positioned nucleosomes on the maternally derived allele. Moreover, it was demonstrated that the unmethylated ICR functions as a unidirectional chromatin insulator, which involves the chromatin insulator protein CTCF.

    The methylated and unmethylated states of the paternal and maternal H19 ICR alleles are known to be stably propagated in the soma throughout development. During in vitro organogenesis, however, the stability of the H19 ICR was demonstrated to be disturbed due to presence of environmental cues. The methylation plasticity of the H19 ICR was nevertheless tolerated without affecting the imprinted status of either Igf2 or H19 genes.

    It was also observed that some human cancer cell lines possess strong de novo methylation activities. Following transfection of an episomal construct, which contains the H19 miningene with the core H19 ICR and its human counterpart, the H19 reporter gene became rapidly do novo methylated and eventually silenced in choriocarcinoma cells (JEG-3), but not in heptoma cells (HEP3B). Although the H19 ICR was initially protected from being methylated by JEG3 cells, progressive waves of de novo methylation generated a heavily methylated H19 ICR in later passages, with concomitant loss of its insulator function.

    It is generally accepted that parental marks undergo erasure and reestablishment during gametogenesis. It was shown that CTCF and its paralogue, BORIS, are expressed in reciprocal patterns during adult male germline development. By means of laser-dissection and bisulfite genomic sequencing, it was observed that de novo methylation of CTCF target sites occurred in BORIS-expressing spermatocytes that exhibit repression of CTCF gene. It was also shown, by chromatin immunopurification analyses of adult mouse testes, that CTCF and BORIS were associated with H19 ICR. A model is proposed to explain the acquisition of differential methylation marks in molecular terms.

  • 23.
    Mukhopadhyay, R
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Whitehead, J
    Lezcano, M
    Yu, W
    Mattsson, A
    Ohlsson, R
    Lineage-specific patterns of occupancy for target sites of the chromatin insulator protein CTCFManuscript (Other academic)
  • 24.
    Mukhopadhyay, Rituparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Chromatin Insulators and CTCF: Architects of Epigenetic States during Development.2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A controlled and efficient coordination of gene expression is the key for normal development of an organism. In mammals, a subset of autosomal genes is expressed monoallelically depending on the sex of the transmitting parent, a phenomenon known as genomic imprinting.

    The imprinted state of the H19 and Igf2 genes is controlled by a short stretch of sequences upstream of H19 known as the imprinting control region (ICR). This region is differentially methylated and is responsible for the repression of the maternally inherited Igf2 allele. It harbors hypersensitive sites on the unmethylated maternal allele and functions as an insulator that binds a chromatin insulator protein CTCF. Hence the H19 ICR, which plays an important role in maintaining the imprinting status of H19 and Igf2, was shown to lose the insulator property upon CpG methylation.

    Another ICR in the Kcnq1 locus regulates long-range repression of p57Kip2 and Kcnq1 on the paternal allele, and is located on the neighboring subdomain of the imprinted gene cluster containing H19 and Igf2, on the distal end of mouse chromosome 7. Similarly to the H19 ICR, the Kcnq1 ICR appears to possess a unidirectional and methylation-sensitive chromatin insulator property in two different somatic cell types. Hence, methylation dependent insulator activity emerges as a common feature of imprinting control regions.

    The protein CTCF is required for the interpretation and propagation of the differentially methylated status of the H19 ICR. Work in this thesis shows that this feature applies genomewide. The mapping of CTCF target sites demonstrated not only a strong link between CTCF, formation of insulator complexes and maintaining methylation-free domains, but also a network of target sites that are involved in pivotal functions. The pattern of CTCF in vivo occupancy varies in a lineage-specific manner, although a small group of target sites show constitutive binding.

    In conclusion, the work of this thesis shows that epigenetic marks play an important role in regulating the insulator property. The studies also confirm the importance of CTCF in maintaining methylation-free domains and its role in insulator function. Our study unravels a new range of target sites for CTCF involved in divergent functions and their developmental control.

    List of papers
    1. CpG methylation regulates the Igf2/H19 insulator
    Open this publication in new window or tab >>CpG methylation regulates the Igf2/H19 insulator
    Show others...
    2001 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 11, no 14, p. 1128-1130Article in journal (Refereed) Published
    Abstract [en]

    The differentially methylated 5'-flank of the mouse H19 gene unidirectionally regulates the communication between enhancer elements and gene promoters and presumably represses maternal Igf2 expression in vivo [1-6]. The specific activation of the paternally inherited Igf2 allele has been proposed to involve methylation-mediated inactivation of the H19 insulator function during male germline development [1-4, 6]. Here, we addressed the role of methylation by inserting a methylated fragment of the H19-imprinting control region (ICR) into a nonmethylated episomal H19 minigene construct, followed by the transfection of ligation mixture into Hep3B cells. Individual clones were expanded and analyzed for genotype, methylation status, chromatin conformation, and insulator function. The results show that the methylated status of the H19 ICR could be propagated for several passages without spreading into the episomal vector. Moreover, the nuclease hypersensitive sites, which are typical for the maternally inherited H19 ICR allele [1], were absent on the methylated ICR, underscoring the suggestion that the methylation mark dictates parent of origin-specific chromatin conformations [1] that involve CTCF [2]. Finally, the insulator function was strongly attenuated in stably maintained episomes. Collectively, these results provide the first experimental support that the H19 insulator function is regulated by CpG methylation.

    Keywords
    Alleles, Animals, Cell Line, CpG Islands, DNA Methylation, Female, Genomic Imprinting, Male, Mice, Plasmids/genetics, RNA; Untranslated/*genetics
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90356 (URN)10.1016/S0960-9822(01)00314-1 (DOI)11509237 (PubMedID)
    Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2017-12-14Bibliographically approved
    2. A differentially methylated imprinting control region within the Kcnq1 locus harbors a methylation-sensitive chromatin insulator.
    Open this publication in new window or tab >>A differentially methylated imprinting control region within the Kcnq1 locus harbors a methylation-sensitive chromatin insulator.
    Show others...
    2002 In: JBC, Vol. 277, p. 18106-18110Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91687 (URN)
    Available from: 2004-04-20 Created: 2004-04-20Bibliographically approved
    3. The Binding Sites for the Chromatin Insulator Protein CTCF Map to DNA Methylation-Free Domains Genome-Wide
    Open this publication in new window or tab >>The Binding Sites for the Chromatin Insulator Protein CTCF Map to DNA Methylation-Free Domains Genome-Wide
    Show others...
    2004 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 14, no 8, p. 1594-1602Article in journal (Refereed) Published
    Abstract [en]

    All known vertebrate chromatin insulators interact with the highly conserved, multivalent 11-zinc finger nuclear factor CTCF to demarcate expression domains by blocking enhancer or silencer signals in a position-dependent manner. Recent observations document that the properties of CTCF include reading and propagating the epigenetic state of the differentially methylated H19 imprinting control region. To assess whether these findings may reflect a universal role for CTCF targets, we identified more than 200 new CTCF target sites by generating DNA microarrays of clones derived from chromatin-immunopurified (ChIP) DNA followed by ChIP-on-chip hybridization analysis. Target sites include not only known loci involved in multiple cellular functions, such as metabolism, neurogenesis, growth, apoptosis, and signalling, but potentially also heterochromatic sequences. Using a novel insulator trapping assay, we also show that the majority of these targets manifest insulator functions with a continuous distribution of stringency. As these targets are generally DNA methylation-free as determined by antibodies against 5-methylcytidine and a methyl-binding protein (MBD2), a CTCF-based network correlates with genome-wide epigenetic states.

    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-91998 (URN)10.1101/gr.2408304 (DOI)15256511 (PubMedID)
    Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2017-12-14Bibliographically approved
    4. Lineage-specific patterns of occupancy for target sites of the chromatin insulator protein CTCF
    Open this publication in new window or tab >>Lineage-specific patterns of occupancy for target sites of the chromatin insulator protein CTCF
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91689 (URN)
    Available from: 2004-04-20 Created: 2004-04-20 Last updated: 2010-01-13Bibliographically approved
  • 25. Ng, M Y M
    et al.
    Levinson, D F
    Faraone, S V
    Suarez, B K
    DeLisi, L E
    Arinami, T
    Riley, B
    Paunio, T
    Pulver, A E
    Irmansyah,
    Holmans, P A
    Escamilla, M
    Wildenauer, D B
    Williams, N M
    Laurent, C
    Mowry, B J
    Brzustowicz, L M
    Maziade, M
    Sklar, P
    Garver, D L
    Abecasis, G R
    Lerer, B
    Fallin, M D
    Gurling, H M D
    Gejman, P V
    Lindholm, E
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Moises, H W
    Byerley, W
    Wijsman, E M
    Forabosco, P
    Tsuang, M T
    Hwu, H-G
    Okazaki, Y
    Kendler, K S
    Wormley, B
    Fanous, A
    Walsh, D
    O'Neill, F A
    Peltonen, L
    Nestadt, G
    Lasseter, V K
    Liang, K Y
    Papadimitriou, G M
    Dikeos, D G
    Schwab, S G
    Owen, M J
    O'Donovan, M C
    Norton, N
    Hare, E
    Raventos, H
    Nicolini, H
    Albus, M
    Maier, W
    Nimgaonkar, V L
    Terenius, L
    Mallet, J
    Jay, M
    Godard, S
    Nertney, D
    Alexander, M
    Crowe, R R
    Silverman, J M
    Bassett, A S
    Roy, M-A
    Mérette, C
    Pato, C N
    Pato, M T
    Roos, J Louw
    Kohn, Y
    Amann-Zalcenstein, D
    Kalsi, G
    McQuillin, A
    Curtis, D
    Brynjolfson, J
    Sigmundsson, T
    Petursson, H
    Sanders, A R
    Duan, J
    Jazin, E
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Myles-Worsley, M
    Karayiorgou, M
    Lewis, C M
    Meta-analysis of 32 genome-wide linkage studies of schizophrenia2009In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, no 8, p. 774-785Article in journal (Refereed)
    Abstract [en]

    A genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 Mb) and 2q (103-134 Mb). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 Mb) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 Mb). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.

  • 26.
    Pant, Vinod
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    CTCF and Epigenetic Regulation of the H19/Igf2 Locus2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An overall coordination between the expressions of genes is required for the proper development of an individual. Although most genes are expressed from both the constituent alleles of the genome, a small subset of autosomal genes are preferentially expressed from only one of the parental alleles, a phenomenon known as genomic imprinting.

    The imprinted H19 and Igf2 genes are considered paradigms of genomic imprinting as their monoallelic expression pattern is coordinated by a short stretch of sequence located upstream of H19, known as the imprinting control region (ICR). This region shows differential methylation, with hypermethylation specifically on the paternal allele. On the maternal allele this region acts as an insulator and harbours maternal specific hypersensitive sites.

    The hypersensitive sites were identified as the result of association of the vertebrate insulator protein CTCF with the region. This association was investigated in both an in vitro episomal system and in an in vivo mouse model system by mutating the CTCF target sites at the H19 ICR. The importance of CTCF for the insulator property of the region was confirmed in both instances. In the mouse model, the disruption of the binding was also observed to affect the methylation profile of the ICR, which ultimately resulted in the de-repression of the maternal Igf2 allele.

    The relevance of multiple CTCF target sites in higher vertebrates for the proper insulator function was investigated using another knock-in mouse model with mutation at a single CTCF target site in the H19 ICR. The investigation confirmed the cooperation between the target sites for the establishment of a functional insulator on the maternal allele. Target sites in the ICR were also analysed for their differential binding affinity for the CTCF protein.

    The utilisation of the CTCF target sites was examined in different human tumours and cell lines. Methylation analysis conveyed a lack of correlation between the loss of insulator function and methylation status of the ICR with the loss of imprinting (LOI) of IGF2. Investigations also identified a novel mechanism, which neutralised the chromatin insulator function of the H19 ICR without affecting its chromatin conformation. This principle might also help in explaining the loss of IGF2 imprinting observed in some instances.

    In conclusion, this thesis confirms the importance of CTCF in the formation of an epigenetically regulated chromatin insulator at the ICR, which in turn controls the expression pattern of H19 and Igf2. The studies also confirm the role of CTCF in the maintenance of the methylation profile of the region. Investigations into the loss of IGF2 imprinting in human cancer indicate the involvement of other novel mechanisms besides CTCF in the regulation of insulator function.

    List of papers
    1. Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin specific and methylation-sensitive
    Open this publication in new window or tab >>Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin specific and methylation-sensitive
    Show others...
    2000 In: Current Biology, ISSN 0960-9822, Vol. 10, no 14, p. 853-856Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90727 (URN)
    Available from: 2003-09-12 Created: 2003-09-12Bibliographically approved
    2. The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long distance insulation and methylation-free domains
    Open this publication in new window or tab >>The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long distance insulation and methylation-free domains
    Show others...
    2003 In: Genes and Development, ISSN 0890-9369, Vol. 17, no 5, p. 586-590Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90728 (URN)
    Available from: 2003-09-12 Created: 2003-09-12Bibliographically approved
    3. CTCF target sites cooperate to manifest chromatin insulation and methylation-free status at the H19 imprinting control region
    Open this publication in new window or tab >>CTCF target sites cooperate to manifest chromatin insulation and methylation-free status at the H19 imprinting control region
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90729 (URN)
    Available from: 2003-09-12 Created: 2003-09-12Bibliographically approved
    4. The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells : A novel mechanism of loss of IGF2 Imprinting
    Open this publication in new window or tab >>The direct bypass of the chromatin insulator function of the H19 imprinting control region in human cancer cells : A novel mechanism of loss of IGF2 Imprinting
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-90730 (URN)
    Available from: 2003-09-12 Created: 2003-09-12 Last updated: 2010-01-13Bibliographically approved
  • 27.
    Pant, Vinod
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Kurukuti, Srinivasulu
    Mariano, Piero
    Ohlsson, Rolf
    CTCF target sites cooperate to manifest chromatin insulation and methylation-free status at the H19 imprinting control regionArticle in journal (Refereed)
  • 28.
    Pant, Vinod
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Mariano, Piero
    Kanduri, Chandrasekhar
    Mattsson, Anita
    Lobanenkov, Victor
    Heuchel, Rainer
    Ohlsson, Rolf
    The nucleotides responsible for the direct physical contact between the chromatin insulator protein CTCF and the H19 imprinting control region manifest parent of origin-specific long distance insulation and methylation-free domains2003In: Genes and Development, ISSN 0890-9369, Vol. 17, no 5, p. 586-590Article in journal (Refereed)
  • 29.
    Reinius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    mRNA expression of Y-linked transcripts in 12 regions of the prenatal human male brain (Featured Image)2009In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 14, no 11, p. 987-Article in journal (Refereed)
  • 30.
    Reinius, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Leonard, Jennifer A
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Blekhman, Ran
    Merino-Martinez, Roxana
    Gilad, Yoav
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    An evolutionarily conserved sexual signature in the primate brain2008In: PLoS Genetics, ISSN 1553-7390, Vol. 4, no e1000100Article in journal (Refereed)
    Abstract [en]

    The question of a potential biological sexual signature in the human brain is a heavily disputed subject. In order to provide further insight into this issue, we used an evolutionary approach to identify genes with sex differences in brain expression level among primates. We reasoned that expression patterns important to uphold key male and female characteristics may be conserved during evolution. We selected cortex for our studies because this specific brain region is responsible for many higher behavioral functions. We compared gene expression profiles in the occipital cortex of male and female humans (Homo sapiens, a great ape) and cynomolgus macaques (Macaca fascicularis, an old world monkey), two catarrhine species that show abundant morphological sexual dimorphism, as well as in common marmosets ( Callithrix Jacchus, a new world monkey) which are relatively sexually monomorphic. We identified hundreds of genes with sex-biased expression patterns in humans and macaques, while fewer than ten were differentially expressed between the sexes in marmosets. In primates, a general rule is that many of the morphological and behavioral sexual dimorphisms seen in polygamous species, such as macaques, are typically less pronounced in monogamous species such as the marmosets. Our observations suggest that this correlation may also be reflected in the extent of sex-biased gene expression in the brain. We identified 85 genes with common sex-biased expression, in both human and macaque and 2 genes, X inactivation-specific transcript (XIST) and Heat shock factor binding protein 1 ( HSBP1), that were consistently sex-biased in the female direction in human, macaque, and marmoset. These observations imply a conserved signature of sexual gene expression dimorphism in cortex of primates. Further, we found that the coding region of female-biased genes is more evolutionarily constrained compared to the coding region of both male-biased and non sex-biased brain expressed genes. We found genes with conserved sexual gene expression dimorphism in the occipital cortex of humans, cynomolgus macaques, and common marmosets. Genes within sexual expression profiles may underlie important functional differences between the sexes, with possible importance during primate evolution.

  • 31.
    Saetre, Peter
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Emilsson, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Axelsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindholm, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Inflammation-related genes up-regulated in schizophrenia brains2007In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 7, p. 46-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Multiple studies have shown that brain gene expression is disturbed in subjects suffering from schizophrenia. However, disentangling disease effects from alterations caused by medication is a challenging task. The main goal of this study is to find transcriptional alterations in schizophrenia that are independent of neuroleptic treatment. METHODS: We compared the transcriptional profiles in brain autopsy samples from 55 control individuals with that from 55 schizophrenic subjects, subdivided according to the type of antipsychotic medication received. RESULTS: Using global and high-resolution mRNA quantification techniques, we show that genes involved in immune response (GO:0006955) are up regulated in all groups of patients, including those not treated at the time of death. In particular, IFITM2, IFITM3, SERPINA3, and GBP1 showed increased mRNA levels in schizophrenia (p-values from qPCR < or = 0.01). These four genes were co-expressed in both schizophrenic subjects and controls. In-vitro experiments suggest that these genes are expressed in both oligodendrocyte and endothelial cells, where transcription is inducible by the inflammatory cytokines TNF-alpha, IFN-alpha and IFN-gamma. CONCLUSION: Although the modified genes are not classical indicators of chronic or acute inflammation, our results indicate alterations of inflammation-related pathways in schizophrenia. In addition, the observation in oligodendrocyte cells suggests that alterations in inflammatory-related genes may have consequences for myelination. Our findings encourage future research to explore whether anti-inflammatory agents can be used in combination with traditional antipsychotics for a more efficient treatment of schizophrenia.

  • 32.
    Svensson, Kristian
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Walsh, Colum
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Fundele, Reinald
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    Ohlsson, Rolf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
    H19 is imprinted in the choroid plexus and leptomeninges of the mouse foetus1995In: Mechanisms of Development, ISSN 0925-4773, E-ISSN 1872-6356, Vol. 51, no 1, p. 31-37Article in journal (Refereed)
    Abstract [en]

    It has been proposed that either the Igf-2 gene or the H19 gene — but not both — can be expressed from a given chromosome. Igf-2 is known to be biallelically expressed in the choroid plexus and leptomeninges, however, raising the question of whether H19 is down-regulated or absent there. We found by in situ hybridization that H19 is indeed expressed in the choroid plexus and leptomeninges of the developing mouse foetus. Comparison with the expression pattern of Igf-2 showed that the genes are coexpressed in all areas, with the exception of the choroid plexus epithelium. To evaluate whether H19 is also biallelically expressed in these tissues, we microdissected embryos from interspecific crosses and performed RNAse protection analysis on the isolated RNA. This revealed that H19 maintains its imprint in the choroid plexus/leptomeninges, being transcribed from the maternal allele at a level comparable to that in normal liver. We discuss the significance of these results for current models of Igf-2 and H19 imprinting.

  • 33. Thakur, Noopur
    et al.
    Kanduri, Meena
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Holmgren, Claes
    Mukhopadhyay, Rituparna
    Kanduri, Chandrasekhar
    Bidirectional silencing and DNA methylation-sensitive methylation-spreading properties of the Kcnq1 imprinting control region map to the same regions2003In: The journal of biological chemistry, Vol. 278, no 11, p. 9514 - 9519Article in journal (Refereed)
  • 34.
    Ullerås, Erik
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Wilcock, Arwen
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Miller, Stephen J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    Franklin, Gary C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
    The sequential activation and repression of the human PDGF-B gene during chronic hypoxia reveals antagonistic roles for the depletion of oxygen and glucose2001In: Growth Factors, ISSN 0897-7194, E-ISSN 1029-2292, Vol. 19, no 4, p. 233-245Article in journal (Refereed)
    Abstract [en]

    Hypoxia and glucose deprivation, are important during many physiological and pathological processes. Cells respond to these stimuli by activating genes involved in the regulation of metabolism and angiogenesis. Platelet derived growth factor-B (PDGF-B) is involved in the regulation of angiogenesis and tumour progression and is induced by hypoxia. Most known hypoxia-induced genes are activated by the hypoxia inducible factor (HIF-1), via its binding to specific response elements. The mechanism of hypoxic induction and the effect of low glucose on PDGF-B expression have not been characterised. We show that PDGF-B exhibits a novel, biphasic regulation (induction, followed by repression below basal levels) in bladder carcinoma cells cultured under chronic hypoxia. We show that the repression observed after long-term hypoxia is due to glucose-depletion and that this can also abrogate short-term hypoxic induction. This is in contrast to the previous results showing that hypoxia/hypoglycaemia elicit the same response. We also show that a putative hypoxia response element in the PDGF-B promoter is not sufficient for hypoxic induction, although it does function as a hypoxia independent enhancer element in hepatocellular carcinoma cells.

  • 35.
    Åberg, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Axelsson, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics.
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Jiang, Lin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Wetterberg, Lennart
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lindholm, Eva
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Support for schizophrenia susceptibility locus on chromosome 2q detected in a Swedish isolate using a dense map of microsatellites and SNPs2008In: American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, ISSN 1552-485X, Vol. 147B, no 7, p. 1238-44Article in journal (Refereed)
    Abstract [en]

    Extended pedigrees are not only very useful to identify disease genes for rare Mendelian conditions, but they may also help unravel the genetics of complex diseases such as schizophrenia. In this study we performed genome-wide multipoint non-parametric linkage (NPL) score calculations using 825 microsatellites and 5,366 single nucleotide polymorphisms (SNPs), respectively, and searched for haplotypes shared by affected individuals, in three multiplex families including 29 genotyped affected individuals which in total contains 49 relative pairs useful for linkage studies. The most consistent results for microsatellites and SNPs were observed on 2q12.3-q14.1 (NPL scores 2.0, empirical P-value 0.009). However, the overall highest NPL score was observed on chromosome 2q33.3 using SNPs (NPL score 2.2, empirical P-value 0.007). Other chromosomal regions were detected on 5q15-q22.1, with microsatellites (NPL scores 1.7, empirical P-value 0.021) and with SNPs (NPL scores 2.0, empirical P-value 0.010) and on 5q23.1 (NPL score 1.9, empirical P-value 0.012) and 8q24.1-q24.2 (NPL score 2.1, empirical P-value 0.009) when using SNPs. The analysis of extended pedigrees allowed the search for haplotypes inherited identical by decent (IBD) by affected individuals. In all regions with NPL score >1.9 we found haplotypes inherited IBD by multiple cases. However, no common haplotypes were found for affected individuals in all families. In conclusion our NPL results support earlier findings suggesting that 2q and possibly 5q and 8q contain susceptibility loci for schizophrenia. Haplotype sharing in families helped to delimit the detected regions that potentially are susceptibility loci for schizophrenia.

  • 36.
    Åberg, Karolina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolution, Genomics and Systematics, Evolutionary Biology.
    Saetre, Peter
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Jareborg, Niclas
    Jazin, Elena
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
    Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia2006In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 19, p. 7482-7487Article in journal (Refereed)
    Abstract [en]

    The quaking viable mouse mutation (qkv) is a deletion including the 5′ regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNA-binding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68–96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing.

1 - 36 of 36
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