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CTCF Regulates Asynchronous Replication of the Imprinted H19/Igf2 Domain
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology.
2007 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 6, no 4, 450-454 p.Article in journal (Refereed) Published
Abstract [en]

Asynchronous replication during S phase is a universal characteristic of genomically imprinted genes. Replication timing in imprinted domains is determined epigenetically, as it is parent of origin specific, and is seen in the absence of sequence divergence between the two alleles. At the imprinted H19/lgf2 domain, the methylated paternal allele replicates early while the CTCF-bound maternal allele replicates late during S phase. CTCF regulates the allele-specific epigenetic characteristics of this domain, including methylation, transcription and chromosome conformation. Here we show that maternal, but not paternal inheritance of a mutated H19 imprinting control region, lacking functional CTCF binding sites, underlies a late to early switch in replication timing of the maternal H19/ lgf2 domain.

Place, publisher, year, edition, pages
2007. Vol. 6, no 4, 450-454 p.
Keyword [en]
replication timing, CTCF, H19/Igf2, genomic imprinting
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96651ISI: 000245495600013PubMedID: 17329968OAI: oai:DiVA.org:uu-96651DiVA: diva2:171297
Available from: 2008-01-25 Created: 2008-01-25 Last updated: 2011-02-08Bibliographically approved
In thesis
1. Epigenetic Regulation of Replication Timing and Signal Transduction
Open this publication in new window or tab >>Epigenetic Regulation of Replication Timing and Signal Transduction
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Upon fertilization the paternal and maternal genomes unite, giving rise to the embryo, with its unique genetic code. All cells in the human body are derived from the fertilized ovum: hence they all contain (with a few exceptions) the same genetic composition. However, by selective processes, genes are turned on and off in an adaptable, and cell type-specific, manner. The aim of this thesis is to investigate how signals coming from outside the cell and epigenetic factors residing in the cell nucleus, cooperate to control gene expression.

The transforming growth factor-β (TGF-β) superfamily consists of around 30 cytokines, which are essential for accurate gene regulation during embryonic development and adult life. Among these are the ligands TGF-β1 and bone morphogenetic (BMP) -7, which interact with diverse plasma membrane receptors, but signal via partly the same Smad proteins. Smad4 is essential to achieve TGF-β-dependent responses. We observed that by regulating transcription factors such as Id2 and Id3 in a specific manner, TGF-β1 and BMP-7 achieve distinct physiological responses.

Moreover, we demonstrate that CTCF, an insulator protein regulating higher order chromatin conformation, is able to direct transcription by recruiting RNA polymerase II to its target sites. This is the first mechanistic explanation of how an insulator protein can direct transcription, and reveals a link between epigenetic modifications and classical regulators of transcription. We also detected that DNA loci occupied by CTCF replicate late. The timing of replication is a crucial determinant of gene activity. Genes replicating early tend to be active, whereas genes replicating late often are silenced. Thus, CTCF can regulate transcription at several levels. Finally, we detected a substantial cross-talk between CTCF and TGF-β signaling. This is the first time that a direct interplay between a signal transduction pathway and the chromatin insulator CTCF is demonstrated.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 302
Keyword
Cell and molecular biology, Chromatin, CTCF, Epigenetics, Genomic Imprinting, H19, Id, Igf2, Insulator, Replication, Signal Transduction, Smad, TGF-β, Transcription, Cell- och molekylärbiologi
Identifiers
urn:nbn:se:uu:diva-8413 (URN)978-91-554-7069-2 (ISBN)
Public defence
2008-02-15, B41, Uppsala Biomedicinska Centrum, BMC, Husarg. 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2008-01-25 Created: 2008-01-25 Last updated: 2009-03-26Bibliographically approved

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