KAT-Independent Gene Regulation by Tip60 Promotes ESC Self-Renewal but Not Pluripotency.
KAT-Independent Gene Regulation by Tip60 Promotes ESC Self-Renewal but Not Pluripotency.
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DOI：
10.1016/j.celrep.2017.04.001
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发表时间：
2017-04-25
期刊：
影响因子：
8.8
通讯作者：
Fazzio TG
中科院分区：
文献类型：
--
作者：
Acharya D;Hainer SJ;Yoon Y;Wang F;Bach I;Rivera-Pérez JA;Fazzio TG
虽然通常认为组蛋白修饰酶的功能取决于其酶活性，但这一假设仍未经许多因素的检验。在这里，我们发现Tip60 （Kat5）赖氨酸乙酰转移酶（KAT）是胚胎干细胞（ESC）自我更新和着床前发育所必需的，它独立于其KAT活性来执行这些功能。与Tip60缺失的ESCs不同，缺乏kat的ESCs在基因表达、Tip60结合位点的染色质可及性和自我更新方面表现出极小的变化，从而证明了Tip60在ESC维持中具有关键的不依赖kat的作用。相反，缺乏kat的ESCs向中胚层和内胚层的分化受损，显示出kat依赖性的分化功能。与这种表型一致，kat缺陷小鼠胚胎表现出植入后发育缺陷。这些发现确立了Tip60在ESCs和分化过程中可分离的kat依赖性和kat非依赖性功能，揭示了这一重要染色质重塑复合体的复杂调控功能。
Although histone-modifying enzymes are generally assumed to function in a manner dependent on their enzymatic activities, this assumption remains untested for many factors. Here we show the Tip60 (Kat5) lysine acetyltransferase (KAT), which is essential for embryonic stem cell (ESC) self-renewal and pre-implantation development, performs these functions independently of its KAT activity. Unlike ESCs depleted of Tip60, KAT–deficient ESCs exhibited minimal alterations in gene expression, chromatin accessibility at Tip60 binding sites, and self-renewal, thus demonstrating a critical KAT–independent role of Tip60 in ESC maintenance. In contrast, KAT–deficient ESCs exhibited impaired differentiation into mesoderm and endoderm, demonstrating a KAT–dependent function in differentiation. Consistent with this phenotype, KAT–deficient mouse embryos exhibited post-implantation developmental defects. These findings establish separable KAT–dependent and KAT–independent functions of Tip60 in ESCs and during differentiation, revealing a complex repertoire of regulatory functions for this essential chromatin remodeling complex.