TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer
TET enzymes augment activation-induced deaminase (AID) expression via 5-hydroxymethylcytosine modifications at the Aicda superenhancer
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DOI：
10.1126/sciimmunol.aau7523
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发表时间：
2019-04-01
影响因子：
24.8
通讯作者：
Rao, Anjana
中科院分区：
文献类型：
--
作者：
Lio, Chan-Wang J.;Shukla, Vipul;Rao, Anjana
泰特酶是双加氧酶，其通过将5-甲基胞嘧啶的甲基氧化为5-羟甲基胞嘧啶（5 hmC）来促进DNA去甲基化。在这里，我们报告了5 hmC标记的区域，染色质可及性和增强子活性之间的密切对应关系，在B细胞，和一个强大的富集的共识结合基序的碱性区域亮氨酸拉链（bZIP）转录因子在TET响应基因组区域。在功能上，Tet 2和Tet 3通过增强Aicda的表达来调节鼠B细胞中的类别转换重组（CSR），Aicda编码CSR所必需的活化诱导的胞苷脱氨酶（AID）。泰特酶存款5 hmC，促进DNA去甲基化，并保持染色质可及性在两个TET响应增强子元件，TetE 1和TetE 2，位于Aicda基因座的超增强子。我们的数据确定bZIP转录因子，ATF样（BATF）作为一个关键的转录因子参与TET依赖性Aicda的表达。在活化的Batf缺陷型B细胞中，5 hmC不沉积在TetEl处，表明BATF促进泰特募集到该Aicda增强子。我们的研究强调了泰特酶对支持AID表达的重要性，并强调了5 hmC作为一种表观遗传标记，在细胞活化过程中捕获增强子动力学。
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 TetEl 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.