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The 5' flank of mouse H19 in an unusual chromatin conformation unidirectionally blocks enhancer-promoter communication
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Evolutionary Biology, Animal Development and Genetics.
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2000 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 10, no 8, 449-457 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 10, no 8, 449-457 p.
Keyword [en]
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: urn:nbn:se:uu:diva-24765DOI: 10.1016/S0960-9822(00)00442-5PubMedID: 10801414OAI: oai:DiVA.org:uu-24765DiVA: diva2:52539
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Epigenetic Regulation of the H19 Chromatin Insulator in Development and Disease
Open this publication in new window or tab >>Epigenetic Regulation of the H19 Chromatin Insulator in Development and Disease
2003 (English)Doctoral 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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 57 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 825
Keyword
Developmental biology, Utvecklingsbiologi
National Category
Developmental Biology
Research subject
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-3405 (URN)91-554-5589-1 (ISBN)
Public defence
2003-05-16, Lindalsalen, EBC, Uppsala, 14:00
Opponent
Supervisors
Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2011-11-10Bibliographically approved
2. The Functional Significance and Chromatin Organisation of the Imprinting Control Regions of the H19 and Kcnq1 Genes
Open this publication in new window or tab >>The Functional Significance and Chromatin Organisation of the Imprinting Control Regions of the H19 and Kcnq1 Genes
2004 (English)Doctoral 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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 40 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 941
Keyword
Molecular genetics, DNA methylation, Imprinting control region, Chromatin, Insulator, Nucleosome positioning, Genetik
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-4002 (URN)91-554-5878-5 (ISBN)
Public defence
2004-03-19, Lindahlsalen, EBC, Uppsala, 10:00
Opponent
Supervisors
Available from: 2004-02-20 Created: 2004-02-20 Last updated: 2011-11-10Bibliographically approved

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