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Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
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2005 (English)In: Human Molecular Genetics, ISSN 0964-6906, Vol. 14, no 7, 953-965 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2005. Vol. 14, no 7, 953-965 p.
URN: urn:nbn:se:uu:diva-93943OAI: oai:DiVA.org:uu-93943DiVA: diva2:167600
Available from: 2006-01-18 Created: 2006-01-18 Last updated: 2009-04-05Bibliographically approved
In thesis
1. The Epigenetics of Gene Transcription and Higher Order Chromatin Conformation
Open this publication in new window or tab >>The Epigenetics of Gene Transcription and Higher Order Chromatin Conformation
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

It is becoming increasingly clear that long-range control of gene expression is mediated through direct physical interactions between genes and regulatory elements, either intra- or interchromosomally. In addition to transcriptional initiation, formation of active chromatin hubs seem to be crucial for increased transcriptional efficiency as well as insulation from neighbouring heterochromatic environment. Regulatory factors apparently have an important role in organization of such functional modules in a development and differentiated- dependent fashion.

The relevance of trans-acting factors in the ‘choice’ process of X-Chromosome Inactivation (XCI) was highlighted by our observations where CTCF was shown to occupy a homologous position on the active mouse and human Xist/XIST promoters and its binding affinity was altered in familial cases of opposite skewed X-inactivation patterns.

The paradigm of genomic imprinting, i.e. the Igf2-H19 locus, manifests its imprinted states through the H19 Imprinting Control Region (ICR). The repression of the maternal Igf2 allele depends on the insulator properties of the H19 ICR when this interacts with CTCF.

The studies here detected a novel kind of CTCF-dependent tightly closed pocket- like higher order structure exclusively on maternal allele which was found to be essential for imprinted Igf2 expression as well as maintenance of precise epigenetic marks at various Differentially Methylated Regions (DMRs) across this locus.

Despite the highly condensed state of the mitotic chromosome, the insulator protein CTCF was found to constitutively occupy its known target sites. Furthermore, pivotal CTCF-dependent long-range regulatory loops within Igf2-H19 locus were found to survive mitotic compaction and such mechanisms might serve as a novel kind of epigenetic memory to minimize transcriptional chaos and to reset proper expression domains in the daughter cells as soon as cells exit mitosis.

Our observations also suggest that the epigenetic reprogramming of H19 ICR during spermatogenesis is initiated by a CTCF-dependent recruitment of chromatin remodeling factor Lsh to the H19 ICR followed by completion of the imprint acquisition process by a replacement of CTCF with its closely related paralogue termed BORIS.

Overall, this thesis unravels the novel roles for CTCF as an architectural factor in the organization of higher order chromatin conformations and transcriptional regulation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 80 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 138
Developmental biology, DNA-protein interactions, Nuclear organization, Transcriptional regulation, Higher order chromatin conformations, Epigenetic reprogramming, Utvecklingsbiologi
National Category
Developmental Biology
urn:nbn:se:uu:diva-6302 (URN)91-554-6444-0 (ISBN)
Public defence
2006-02-10, Lindahlsalen, Evolutionary Biology Centre, Norbyvägen 18, Uppsala, 13:00 (English)
Available from: 2006-01-18 Created: 2006-01-18 Last updated: 2009-04-05Bibliographically approved

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