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

Shari Orlanski, Verena Labi, Yitzhak Reizel, Adam Spiro, Michal Lichtenstein, Rena Levin-Klein, Sergei B. Koralov, Yael Skversky, Klaus Rajewsky*, Howard Cedar, Yehudit Bergman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylationof 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.

Original languageAmerican English
Pages (from-to)5018-5023
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number18
DOIs
StatePublished - 3 May 2016

Bibliographical note

Funding Information:
We thank Amit Lavon for his help with the computational analysis, Claudia Grosse and Janine Cernoch for technical support, and Emmanuel Derudder for valuable discussions. This research was supported by grants from the European Research Council (Grant 268614 to H.C. and Grant 268921 to K.R.), the Israel Cancer Research Fund (H.C. and Y.B.), the US-Israel Binational Foundation (Y.B.), the Rosetrees Foundation (H.C.), the Israeli Centersof Research Excellence (I-CORE) Program of Israel Science Foundation (ISF) (Y.B. and H.C.), Joint Program between the ISF and the National Natural Science Foundation of China (NSFC) (Y.B.), and the Emanuel Rubin Chair in Medical Science (Y.B.).

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