Template Activating Factor-I α Regulates Retroviral Silencing during Reprogramming
Template Activating Factor-I α Regulates Retroviral Silencing during Reprogramming
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模板激活因子-I α 在重编程过程中调节逆转录病毒沉默
DOI：
10.1016/j.celrep.2019.10.010
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发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Hisatake Koji
中科院分区：
文献类型：
--
作者：
Bui Phuong Linh;Nishimura Ken;Seminario Mondejar Gonzalo;Kumar Arun;Aizawa Shiho;Murano Kensaku;Nagata Kyosuke;Hayashi Yohei;Fukuda Aya;Onuma Yasuko;Ito Yuzuru;Nakanishi Mahito;Hisatake Koji
将体细胞重编程为诱导多能干细胞（iPSC）伴随着表观遗传程序的巨大变化，包括内源性和外源性逆转录病毒的沉默。在这里，我们利用复制缺陷型和持续性仙台病毒（SeVdp）为基础的载体，以监测逆转录病毒沉默过程中重编程。我们观察到逆转录病毒沉默发生在早期重编程阶段，不需要逆转录病毒基因组中的KLF 4或YY 1结合位点。插入染色质免疫沉淀（iChIP）使我们能够分离组装在沉默的前病毒上的因子，包括组蛋白乙酰转移酶（INHAT）抑制剂的组分，其中包括SET/TAF-I癌蛋白。小鼠胚胎成纤维细胞（MEFs）中SET/TAF-I的敲低减少了重编程过程中的逆转录病毒沉默，而模板激活因子-I α（TAF-Iα）（一种在胚胎干细胞（ESCs）中占主导地位的SET/TAF-I亚型）的过表达，通过基于SeVdp的载体增强了逆转录病毒沉默，而这种载体在逆转录病毒沉默方面存在缺陷。我们的结果表明TAF-Iα在重编程过程中逆转录病毒沉默中起重要作用。
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is accompanied by dramatic changes in epigenetic programs, including silencing of endogenous and exogenous retroviruses. Here, we utilized replication-defective and persistent Sendai virus (SeVdp)-based vectors to monitor retroviral silencing during reprogramming. We observed that retroviral silencing occurred at an early reprogramming stage without a requirement for KLF4 or the YY1-binding site in the retroviral genome. Insertional chromatin immunoprecipitation (iChIP) enabled us to isolate factors assembled on the silenced provirus, including components of inhibitor of histone acetyltransferase (INHAT), which includes the SET/TAF-I oncoprotein. Knockdown of SET/TAF-I in mouse embryonic fibroblasts (MEFs) diminished retroviral silencing during reprogramming, and overexpression of template activating factor-I α (TAF-Iα), a SET/TAF-I isoform predominant in embryonic stem cells (ESCs), reinforced retroviral silencing by an SeVdp-based vector that is otherwise defective in retroviral silencing. Our results indicate an important role for TAF-Iα in retroviral silencing during reprogramming.