Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility
- La Jolla Institute For Allergy & Immunology, United States
- Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, China
- La Jolla Institute For Allergy and Immunology, United States
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.
Data availability
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Role of Tet proteins in B cell developmentPublicly available at the NCBI BioProject database (accession no: PRJNA324297).
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Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identitiesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE21512).
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A global network of transcription factors, involving E2A, EBF1 and FOXO1, that orchestrates the B cell fatePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE21978).
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Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartmentPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE31971).
Article and author information
Author details
Chan-Wang Jerry Lio
Funding
Cancer Research Institute (Irvington Postdoctoral Fellowship)
- Chan-Wang Jerry Lio
National Institutes of Health (AI44432)
- Anjana Rao
National Institutes of Health (CA151535)
- Anjana Rao
Leukemia and Lymphoma Society (6187-12)
- Anjana Rao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal works were performed according to protocol (AP128-AR2-0516) approved by the Institutional Animal Care and Use Committee at La Jolla Institute.
Copyright
© 2016, Lio et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility
eLife 5:e18290.
https://doi.org/10.7554/eLife.18290
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