Abstract
TET enzymes are dioxygenases that promote DNA demethylation by oxidizing the methyl group of 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Here, we report a close correspondence between 5hmC-marked regions, chromatin accessibility and enhancer activity in B cells, and a strong enrichment for consensus binding motifs for basic region-leucine zipper (bZIP) transcription factors at TET-responsive genomic regions. Functionally, Tet2 and Tet3 regulate class switch recombination (CSR) in murine B cells by enhancing expression of Aicda, which encodes the activation-induced cytidine deaminase (AID) enzyme essential for CSR. TET enzymes deposit 5hmC, facilitate DNA demethylation, and maintain chromatin accessibility at two TET-responsive enhancer elements, TetE1 and TetE2, located within a superenhancer in the Aicda locus. Our data identify the bZIP transcription factor, ATF-like (BATF) as a key transcription factor involved in TET-dependent Aicda expression. 5hmC is not deposited at TetE1 in activated Batf-deficient B cells, indicating that BATF facilitates TET recruitment to this Aicda enhancer. Our study emphasizes the importance of TET enzymes for bolstering AID expression and highlights 5hmC as an epigenetic mark that captures enhancer dynamics during cell activation.
| Original language | English (US) |
|---|---|
| Article number | eaau7523 |
| Journal | Science Immunology |
| Volume | 4 |
| Issue number | 34 |
| DOIs | |
| State | Published - Apr 26 2019 |
Funding
We would like to thank U. Basu for providing the AID antibody; K. Yu for Aicda-KO CH12F3 cells; H. Singh for splenocytes from Cd19-cre Irf4-flox mice; P. Casali and H. Zan for discussions; L. Hempleman for assisting with animal experiments; C. Kim, L. Nosworthy, D. Hinz, and R. Simmons (LJI Flow Cytometry Core) for cell sorting; J. Day and N. Wlodychak (LJI Functional Genomics Center) for assistance with next-generation sequencing; and S. Bélanger for advice on immunization. C.-W.J.L. was supported by a Cancer Research Institute Irvington Postdoctoral Fellowship and the Independent Investigator Fund (Kyowa Hakko Kirin/LJI). V.S. was supported by a Leukemia and Lymphoma Society Postdoctoral Fellowship (grant ID: 5463-18). D.S.-C. and E.G.A. were supported by the CONACYT/UCMEXUS fellowship from Mexico-US. This work was supported by the National Institutes of Health (NIH) grants R35 CA210043, R01 AI109842, and AI128589 (to A.R.) and R01 AI127642 (to D.G.S.). F.A. and A.C. were partially supported by Institute Leadership Funds from the LJI and by NIH grants R01 MH111267 and R35 GM128938. Purchase of the Illumina HiSeq 2500 and the BD FACSAria II was supported by equipment grants NIH S10OD016262 and NIH S10RR027366, respectively.
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology