Tissue-specific DNA demethylation is required for proper B-cell differentiation and function.
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.
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Shari
S
Orlanski
Max-Delbrück Center for Molecular Medicine, Berlin 13092, Germany; Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Innsbruck 6020, Austria;
Verena
V
Labi
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Yitzhak
Y
Reizel
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Adam
A
Spiro
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Michal
M
Lichtenstein
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Rena
R
Levin-Klein
Department of Pathology, New York University Medical Center, New York, NY 10016.
Sergei B
SB
Koralov
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Yael
Y
Skversky
Max-Delbrück Center for Molecular Medicine, Berlin 13092, Germany; klaus.rajewsky@mdc-berlin.de yehuditb@ekmd.huji.ac.il.
Klaus
K
Rajewsky
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;
Howard
H
Cedar
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120; klaus.rajewsky@mdc-berlin.de yehuditb@ekmd.huji.ac.il.
Yehudit
Y
Bergman
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000235:genetics
D004268:DNA-Binding Proteins
DMRs; Tet2/Tet3; chromatin; differentially methylated regions