title: Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility.
abstract: Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation and generating new epigenetic marks. Here we show that concomitant loss of Tet2 and Tet3 in mice at early B cell stage blocked the pro- to pre-B cell transition in the bone marrow, decreased Irf4 expression and impaired the germline transcription and rearrangement of the Igκ locus. Tet2/3-deficient pro-B cells showed increased CpG methylation at the Igκ 3' and distal enhancers that was mimicked by depletion of E2A or PU.1, as well as a global decrease in chromatin accessibility at enhancers. Importantly, re-expression of the Tet2 catalytic domain in Tet2/3-deficient B cells resulted in demethylation of the Igκ enhancers and restored their chromatin accessibility. Our data suggest that TET proteins and lineage-specific transcription factors cooperate to influence chromatin accessibility and Igκ enhancer function by modulating the modification status of DNA.
authors.affiliation: Division of Signaling and Gene Expression, San Diego, United States.
authors.forename: Chan-Wang
authors.identifier: 0000-0003-3876-6741
authors.initials: CW
authors.lastname: Lio
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Signaling and Gene Expression, San Diego, United States.
authors.forename: Edahí
authors.initials: E
authors.lastname: González-Avalos
authors.affiliation: Division of Signaling and Gene Expression, San Diego, United States.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Hogan
authors.affiliation: Division of Signaling and Gene Expression, San Diego, United States.|Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Sanford Consortium for Regenerative Medicine, San Diego, United States.
authors.forename: Xing
authors.initials: X
authors.lastname: Chang
authors.affiliation: Division of Signaling and Gene Expression, San Diego, United States.|Sanford Consortium for Regenerative Medicine, San Diego, United States.|Department of Pharmacology, University of California, San Diego, San Diego, United States.|Moores Cancer Center, University of California, San Diego, San Diego, United States.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D000099218:Interferon Regulatory Factor-4
chemical_list: D044503:5-Methylcytosine; D002843:Chromatin; D004247:DNA; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D000099218:Interferon Regulatory Factor-4; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse
keywords: 5hmC; B cell development; DNA methylation; Tet proteins; chromosomes; genes; immunology; mouse