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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.
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Evolutionary Biology, Department of Animal Development and Genetics.
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URN: urn:nbn:se:uu:diva-90358OAI: oai:DiVA.org:uu-90358DiVA: diva2:162683
Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2010-01-13Bibliographically 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.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 825
Developmental biology, Utvecklingsbiologi
National Category
Developmental Biology
Research subject
Developmental Biology
urn:nbn:se:uu:diva-3405 (URN)91-554-5589-1 (ISBN)
Public defence
2003-05-16, Lindalsalen, EBC, Uppsala, 14:00
Available from: 2003-04-24 Created: 2003-04-24 Last updated: 2011-11-10Bibliographically approved

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