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Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
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2004 (English)In: Nature Genetics, ISSN 1061-4036, Vol. 36, no 10, 1105-1110 p.Article in journal (Refereed) Published
Abstract [en]

Chromatin insulators demarcate expression domains by blocking the cis effects of enhancers or silencers in a position-dependent manner1, 2. We show that the chromatin insulator protein CTCF carries a post-translational modification: poly(ADP-ribosyl)ation. Chromatin immunoprecipitation analysis showed that a poly(ADP-ribosyl)ation mark, which exclusively segregates with the maternal allele of the insulator domain in the H19 imprinting control region, requires the bases that are essential for interaction with CTCF3. Chromatin immunoprecipitation−on−chip analysis documented that the link between CTCF and poly(ADP-ribosyl)ation extended to more than 140 mouse CTCF target sites. An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity. We suggest that poly(ADP-ribosyl)ation imparts chromatin insulator properties to CTCF at both imprinted and nonimprinted loci, which has implications for the regulation of expression domains and their demise in pathological lesions.

Place, publisher, year, edition, pages
2004. Vol. 36, no 10, 1105-1110 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95337DOI: 10.1038/ng1426OAI: oai:DiVA.org:uu-95337DiVA: diva2:169511
Available from: 2007-01-10 Created: 2007-01-10 Last updated: 2013-05-16Bibliographically approved
In thesis
1. Epigenetic Regulation of Genomic Imprinting and Higher Order Chromatin Conformation
Open this publication in new window or tab >>Epigenetic Regulation of Genomic Imprinting and Higher Order Chromatin Conformation
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Epigenetisk reglering av genetisk prägling och kromatinets konformation
Abstract [en]

The genetic information encoded by the DNA sequence, can be expressed in different ways. Genomic imprinting is an epigenetic phenomenon that results in monoallelic expression of imprinted genes in a parent of origin-dependent manner. Imprinted genes are frequently found in clusters and can share common regulatory elements. Most of the imprinted genes are regulated by Imprinting Control Regions (ICRs). H19/Igf2 region is a well known imprinted cluster, which is regulated by insulator function of ICR located upstream of the H19 gene. It has been proposed that the epigenetic control of the insulator function of H19 ICR involves organization of higher order chromatin interactions.

In this study we have investigated the role of post-translational modification in regulating insulator protein CTCF (CCCTC-binding factor). The results indicated novel links between poly(ADP-ribosyl)ation and CTCF, which are essential for regulating insulators function.

We also studied the higher order chromatin conformation of Igf2/H19 region. The results indicated there are different chromatin structures on the parental alleles. We identified CTCF-dependent loop on the maternal allele which is different from the paternal chromatin and is essential for proper imprinting of Igf2 and H19 genes. The interaction of H19 ICR with Differentially Methylated Regions (DMRs) of Igf2 in a parent-specific manner maintains differential epigenetic marks on maternal and paternal alleles.

The results indicate that CTCF occupies specific sites on highly condensed mitotic chromosomes. CTCF-dependent long-range key interaction on the maternal allele is maintained during mitosis, suggesting the possible epigenetic memory of dividing cells.

In this study, we developed a new method called Circular Chromosome Conformation Capture (4C) to screen genome-wide interactions with H19 ICR. The results indicated there are wide intra- and inter-chromosomal interactions which are mostly dependent on CTCF-binding site at H19 ICR.

These observations suggest new aspects of epigenetic regulation of the H19/Igf2 imprinted region and higher order chromatin structure.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 262
Keyword
Developmental biology, Epigenetic, Imprinting, Chromatin, CTCF, H19 ICR, 4C, Utvecklingsbiologi
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-7435 (URN)978-91-554-6772-2 (ISBN)
Public defence
2007-01-31, Lindahlsalen, EBC, Norbyvägen 18A, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2007-01-10 Created: 2007-01-10 Last updated: 2010-01-08Bibliographically approved
2. Genomic Imprinting in Development and Evolution
Open this publication in new window or tab >>Genomic Imprinting in Development and Evolution
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genetic information is encoded by the linear sequence of the DNA double helix, while epigenetic information is overlayed as the packaging of DNA and associated proteins into the chromatin structure. Variations in chromatin structure play a vital role in establishing and maintaining patterns of gene expression during differentiation and development of higher eukaryotes, and disruption of this epigenetic gene regulation can lead to cancer. Mammals display an epigenetic phenomenon known as genomic imprinting, which provides an ideal model system for the study of epigenetics. Genes subject to genomic imprinting are differentially expressed within a single cell depending on the parental origin of the chromosome. Imprinting of the maternally expressed H19 gene and the adjacent paternally expressed Igf2 gene is regulated by the chromatin insulator protein CTCF. The studies presented in this thesis aim to investigate the functional mechanisms of CTCF-dependent gene regulation at the H19/Igf2 locus and at numerous other target sites throughout the genome. We have investigated the role of CTCF and a related protein BORIS in establishing the maternal to paternal imprint transition in chromatin structure at the H19/Igf2 locus in the male germline. We have developed novel microarray based methods to identify and characterize numerous new CTCF target sites throughout the mouse genome. We have shown that CTCF acts as part of the RNA polymerase II complex. We have identified the post-translational modification by addition of ADP-ribose polymers to CTCF, and demonstrated that this modification regulates its insulating ability. The results of these studies of CTCF-dependent epigenetic gene regulation are discussed in light of the evolution of genomic imprinting and chromatin insulators, and a novel role for poly ADP-ribosylation of CTCF in the progression of cancer is proposed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 74 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 1000
Keyword
Developmental biology, Utvecklingsbiologi
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-4491 (URN)91-554-6015-1 (ISBN)
Public defence
2004-09-22, Lindahlsalen, Evolutionary Biology Centre, Norbyvägen 18A, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2004-09-01 Created: 2004-09-01 Last updated: 2013-05-16Bibliographically approved

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