Research ArticleIMMUNOGENOMICS

TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer

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Science Immunology  26 Apr 2019:
Vol. 4, Issue 34, eaau7523
DOI: 10.1126/sciimmunol.aau7523

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Epigenetic enablers of B cell activation

Initiation of immunoglobulin class switching and somatic hypermutation during B cell activation requires tightly regulated expression of the activation-induced cytidine deaminase (Aicda) gene. Lio et al. investigated how the TET2 and TET3 enzymes, responsible for depositing 5-hydroxymethylcytosine epigenetic marks on genomic DNA, contribute to regulation of Aicda expression by studying B cells from mice in which the two enzymes can be inducibly deleted. This analysis identified two key elements (TetE1 and TetE2) within the Aicda superenhancer that are marked by TET2 and TET3 for progressive hydroxymethylation followed by demethylation, thereby facilitating chromatin accessibility and Aicda expression. The results demonstrate that kinetic mapping of 5-hydroxymethylcytosine on genomic DNA is a powerful tool for identification of key sites of active gene transcription during lymphocyte activation and differentiation.

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.

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