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Tissue-specific DNA demethylation is required for proper B-cell differentiation and function.

ABSTRACT: There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylation of specific sites that vary between cell types. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes. We show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the expression of nearby B-cell lineage genes by impairing enhancer activity, thus causing defects in B-cell differentiation and function. Thus, tissue-specific DNA demethylation appears to be necessary for proper somatic cell development in vivo.

SUBMITTER: Orlanski S

PROVIDER: S-EPMC4983829 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Tissue-specific DNA demethylation is required for proper B-cell differentiation and function.

Orlanski Shari S Labi Verena V Reizel Yitzhak Y Spiro Adam A Lichtenstein Michal M Levin-Klein Rena R Koralov Sergei B SB Skversky Yael Y Rajewsky Klaus K Cedar Howard H Bergman Yehudit Y

Proceedings of the National Academy of Sciences of the United States of America 20160418 18

There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylation of specific sites that vary between cell types. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes. We show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the e ...[more]

PMID: 27091986

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Tissue specific demethylation is required for proper B-cell differentiation and function

Project description:Many studies have demonstrated that somatic cell differentiation during development is accompanied by extensive demethylation of specific sites relevant to each cell type. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes [Ziller, 2013 #5787]. In this paper, we show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the expression of nearby B-cell lineage genes, probably by inhibiting enhancer activity, thus causing defects in B- cell differentiation. Our studies represent the first demonstration that tissue-specific demethylation may be necessary for proper development in vivo. DNA methylation profile of different developmental stages of B-cells isolated from wild-type or Tet2/Tet3 single and double knock out. The data was generated using the RRBS protocol followed by deep sequncing. RNAseq was performed on these samples as well.

2016-04-06 | E-GEOD-70538 | biostudies-arrayexpress

Tissue specific demethylation is required for proper B-cell differentiation and function

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SUMOylation Coordinates BERosome Assembly in Active DNA Demethylation During Cell Differentiation

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