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A differentially methylated imprinting control region within the Kcnq1 Locus harbors a methylation-sensitive chromatin insulator
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för evolutionsbiologi, Zoologisk utvecklingsbiologi.
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2002 Ingår i: The Journal of biological chemistry, Vol. 277, nr 20, s. 18106 - 18110Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2002. Vol. 277, nr 20, s. 18106 - 18110
Identifikatorer
URN: urn:nbn:se:uu:diva-91381OAI: oai:DiVA.org:uu-91381DiVA, id: diva2:164092
Tillgänglig från: 2004-02-20 Skapad: 2004-02-20Bibliografiskt granskad
Ingår i avhandling
1. The Functional Significance and Chromatin Organisation of the Imprinting Control Regions of the H19 and Kcnq1 Genes
Öppna denna publikation i ny flik eller fönster >>The Functional Significance and Chromatin Organisation of the Imprinting Control Regions of the H19 and Kcnq1 Genes
2004 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2004. s. 40
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 941
Nyckelord
Molecular genetics, DNA methylation, Imprinting control region, Chromatin, Insulator, Nucleosome positioning, Genetik
Nationell ämneskategori
Genetik
Identifikatorer
urn:nbn:se:uu:diva-4002 (URN)91-554-5878-5 (ISBN)
Disputation
2004-03-19, Lindahlsalen, EBC, Uppsala, 10:00
Opponent
Handledare
Tillgänglig från: 2004-02-20 Skapad: 2004-02-20 Senast uppdaterad: 2011-11-10Bibliografiskt granskad

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