Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility

Abstract
Data availability
Article and author information
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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

The following data sets were generated

(2016) Role of Tet proteins in B cell development
Publicly available at the NCBI BioProject database (accession no: PRJNA324297).

http://www.ncbi.nlm.nih.gov/bioproject/PRJNA324297

The following previously published data sets were used

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(2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE21512).

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21512
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(2010) A global network of transcription factors, involving E2A, EBF1 and FOXO1, that orchestrates the B cell fate
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE21978).

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE21978
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Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE31971).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31971

Article and author information

Author details

Chan-Wang Jerry Lio

Division of Signaling and Gene Expression, La Jolla Institute For Allergy & Immunology, San Diego, United States

For correspondence
lio@lji.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3876-6741
Jiayuan Zhang

Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China

Competing interests
The authors declare that no competing interests exist.
Edahí González-Avalos

Division of Signaling and Gene Expression, La Jolla Institute For Allergy and Immunology, San Diego, United States

Competing interests
The authors declare that no competing interests exist.
Patrick G Hogan

Division of Signaling and Gene Expression, La Jolla Institute For Allergy and Immunology, San Diego, United States

Competing interests
The authors declare that no competing interests exist.
Xing Chang

Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China

For correspondence
changxing@sibs.ac.cn

Competing interests
The authors declare that no competing interests exist.
Anjana Rao

Division of Signaling and Gene Expression, La Jolla Institute For Allergy and Immunology, San Diego, United States

For correspondence
arao@lji.org

Competing interests
The authors declare that no competing interests exist.

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

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.