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The epigenome is stress-sensitive
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
(English)Manuscript (Other (popular science, discussion, etc.))
URN: urn:nbn:se:uu:diva-94975OAI: oai:DiVA.org:uu-94975DiVA: diva2:169015
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2010-01-14Bibliographically approved
In thesis
1. The Control of the Epigenome
Open this publication in new window or tab >>The Control of the Epigenome
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The genetic information required for the existence of a living cell of any kind is encoded in the sequence information scripted in the double helix DNA. A modern trend in biology struggles to come to grip with the amazing fact that there are so many different cell types in our body and that they are directed from the same genomic blueprint. It is clear, that the key to this feature is provided by epigenetic information that dictates how, where and when genes should be expressed. Epigenetic states “dress up” the genome by packaging it in chromatin conformations that differentially regulate accessibility for key nuclear factors and in coordination with differential localizations within the nucleus will dictate the ultimate task, expression.

In the imprinted Igf2/H19 domain, this feature is determined by the interaction between the chromatin insulator protein CTCF and the unmethylated H19 imprinting control region. Here I show that CTCF interacts with many sites genome-wide and that these sites are generally protected from DNA methylation, suggesting that CTCF function has been recruited to manifest novel imprinted states during mammalian development.

This thesis also describes the discovery of an epigenetically regulated network of intra and interchromosomal complexes, identified by the invented 4C method. Importantly, the disruption of CTCF binding sites at the H19 imprinting control region not only disconnects this network, but also leads to significant changes in expression patterns in the interacting partners.

Interestingly, CTCF plays an important role in the regulation of the replication timing not only of the Igf2 gene, but also of all other sequences binding this factor potentially by a cell cycle-specific relocation of CTCF-DNA complexes to subnuclear compartments.

Finally, I show that epigenetic marks signifying active or inactive states can be gained and lost, respectively, upon exposure to stress. As many genes belonging to the apoptotic pathway are upregulated we propose that stress-induced epigenetic lesions represent a surveillance system marking the affected cells for death to the benefit of the individual. This important observation opens our minds to the view of new intrinsic mechanisms that the cell has in order to maintain proper gene expression, and in the case of misleads there are several check points that direct the cell to towards important survival decisions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 64 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 230
Biology, Epigenetics, chromosome interactions, replication timing, histone modifications, epigenetic surveillance, Biologi
National Category
Biological Sciences
urn:nbn:se:uu:diva-7190 (URN)91-554-6680-X (ISBN)
Public defence
2006-10-31, Lindahlsalen, EBC, Nörbyvagen 18a, uppsala, 13:00 (English)
Available from: 2006-10-10 Created: 2006-10-10 Last updated: 2011-05-17Bibliographically approved

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