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The 4C technique: the ‘Rosetta stone’ for genome biology in 3D?
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (Rolf Ohlsson)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (Rolf Ohlsson)
2007 (English)In: Current Opinion in Cell Biology, ISSN 0955-0674, E-ISSN 1879-0410, Vol. 19, no 3, 321-325 p.Article in journal (Refereed) Published
Abstract [en]

Despite considerable efforts, the spatial link between the nuclear architecture and the genome remains enigmatic. The 4C method, independently innovated in four different laboratories, might in combination with other methods change that. As this method is based on the unbiased identification of sequences interacting with specific baits, there are unique opportunities for unravelling the secrets of how the genome functions in 3D.

Place, publisher, year, edition, pages
2007. Vol. 19, no 3, 321-325 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96392DOI: 10.1016/j.ceb.2007.04.008ISI: 000247775200012OAI: oai:DiVA.org:uu-96392DiVA: diva2:170951
Available from: 2007-10-31 Created: 2007-10-31 Last updated: 2011-02-01Bibliographically approved
In thesis
1. Epigenetic Regulation of Higher Order Chromatin Conformations and Gene Transcription
Open this publication in new window or tab >>Epigenetic Regulation of Higher Order Chromatin Conformations and Gene Transcription
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Epigenetic states constitute heritable features of the chromatin to regulate when, where and how genes are expressed in the developing conceptus. A special case of epigenetic regulation, genomic imprinting, is defined as parent of origin-dependent monoallelic expression. The Igf2-H19 locus is considered as paradigm of genomic imprinting with a growth-promoting gene, Igf2, expressed paternally and a growth antagonist, H19 encoding a non-coding transcript, expressed only from the maternal allele. The monoallelic expression patterns are regulated by the epigenetic status at an imprinting control region (ICR) in the 5´-flank of the H19 gene. The chromatin insulator protein CTCF interacts with only the maternal H19 ICR allele to prevent downstream enhancers to communicate with the Igf2 promoters. Mutations of these CTCF binding sites lead to biallelic Igf2 expression, increased size of the conceptus and predisposition for cancer.

Reasoning that these effects cannot be explained by the regulation of Igf2 expression alone, a technique was invented to examine long-range chromatin interactions without prior knowledge of the interacting partners. Applying the circular chromosomal conformation capture (4C) technique to mouse neonatal liver cells, it was observed that 114 unique sequences interacted with the H19 ICR. A majority of these interactors was in complex with only the maternal H19 ICR allele and depended on the presence of functional CTCF binding sites. The functional consequence of chromosomal networks was demonstrated by the observation that the maternal H19 ICR allele regulated the transcription of two genes on another chromosome. As the chromosomal networks underwent reprogramming during the maturation of embryonic stem cells, attention was turned to human cancer cells, displaying features common with mouse embryonic stem cells. Subsequently, chromatin folding at the human H19 ICR suggested that stable chromatin loops were organized by synergistic interactions within and between baits and interactors. The presence of these interactions was linked to DNA methylation patterns involving repeat elements. A "flower" model of chromatin networks was formulated to explain these observations.

This thesis has unravealed a novel feature of the epigenome and its functions to regulate gene expression in trans. The identified roles for CTCF as an architectural factor in the organization of higher order chromatin conformations may be of importance in understanding development and disease ontogeny from novel perspectives.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 359
Keyword
Developmental biology, Genomic imprinting, Chromatin, Epigenetics, Cancer
National Category
Developmental Biology
Identifiers
urn:nbn:se:uu:diva-8296 (URN)978-91-554-7012-8 (ISBN)
Public defence
2007-11-24, Lindahlssalen, House nr 5, Norbyvägen 18A, EBC, 10:00 (English)
Opponent
Supervisors
Available from: 2007-10-31 Created: 2007-10-31 Last updated: 2009-04-05Bibliographically approved

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