AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes.
AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes.
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DOI：
10.1038/nature12299
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发表时间：
2013-08-01
期刊：
影响因子：
64.8
通讯作者：
Evans, Todd
中科院分区：
文献类型：
--
作者：
Kumar, Ritu;DiMenna, Lauren;Schrode, Nadine;Liu, Ting-Chun;Franck, Philipp;Munoz-Descalzo, Silvia;Hadjantonakis, Anna-Katerina;Zarrin, Ali A.;Chaudhuri, Jayanta;Elemento, Olivier;Evans, Todd
激活诱导的胞苷脱氨酶（AID）是免疫球蛋白基因座处的体细胞超突变和类别转换重组所必需的。在GC-B细胞中，AID高度表达，具有固有的增变因子活性，有助于产生抗体多样性。然而，AID也可以通过直接脱氨基5-甲基胞嘧啶（5 mC）与碱基切除修复交换胞嘧啶来调节基因表达。这条通路促进基因去甲基化，从而消除表观遗传记忆。例如，AID促进原始生殖细胞中基因组的主动去甲基化。然而，不同的研究表明，在与胚胎干细胞（ESC）融合后，AID促进体细胞核中的多能性的功能的需要或缺乏。我们通过比较缺乏AID的细胞从分化细胞类型重编程为诱导多能干细胞（iPSC）的相对能力，直接测试了AID是否调节表观遗传记忆。我们表明，艾滋病无效细胞是短暂的高度反应的重编程过程。虽然它们启动多能性基因的表达，但它们不能稳定多能性状态。AIDS无效细胞的基因组在重编程细胞中保持高度甲基化，并且与多能性相关的高度甲基化基因未能稳定上调，包括许多MYC靶基因。最近的研究确定了与甲基化状态相关的重编程的后期步骤，并涉及多能性网络组件的第二组。AID调节这一后期步骤，消除表观遗传记忆以稳定多能状态。
The activation-induced cytidine deaminase enzyme (AID) is required for somatic hyper-mutation and class switch recombination at the immunoglobulin locus. In GC-B cells, AID is highly expressed, with inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine (5mC) in concert with base excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID promoting pluripotency in somatic nuclei following fusion with embryonic stem cells (ESCs). We tested directly whether AID regulates epigenetic memory, by comparing the relative ability of cells lacking AID to reprogram from a differentiated cell type to an induced pluripotent stem cell (iPSC). We show that AID-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize the pluripotent state. The genome of AID-null cells remains hyper-methylated in reprogramming cells, and hyper-methylated genes associated with pluripotency fail to be stably up-regulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.
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影响因子：
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影响因子：
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胚胎干细胞通过双相重编程在体细胞融合中诱导多能性。
影响因子：
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作者：
Foshay KM;Looney TJ;Chari S;Mao FF;Lee JH;Zhang L;Fernandes CJ;Baker SW;Clift KL;Gaetz J;Di CG;Xiang AP;Lahn BT
通讯作者：
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64.8
作者：
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通讯作者：
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