An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells.
An Mll4/COMPASS-Lsd1 epigenetic axis governs enhancer function and pluripotency transition in embryonic stem cells.
复制标题
DOI：
10.1126/sciadv.aap8747
复制
发表时间：
2018-01
期刊：
影响因子：
13.6
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Cao K;Collings CK;Morgan MA;Marshall SA;Rendleman EJ;Ozark PA;Smith ER;Shilatifard A
增强子处共激活子和共阻遏子复合物之间的平衡指示干细胞多能性转变。染色质调节剂通过协调动态发育基因表达程序来控制细胞分化，因此，染色质状态调节中的故障有助于发育障碍和疾病状态。M114（Kmt 2d）是COMPASS（与Set 1相关的蛋白复合体）蛋白家族的成员，其在增强子处实现组蛋白H3赖氨酸4单甲基化（H3 K4 me 1），对于胚胎发育是必需的，并且作为泛癌肿瘤抑制剂发挥功能。我们定义的作用Mll 4/COMPASS和它的催化活性在维持和退出的基态多能性小鼠胚胎干细胞（ESCs）。M114是ESC退出幼稚多能状态所需的;然而，其内在的催化活性对于该过程是不确定的。H3 K4脱甲基酶Lsd 1（Kdm 1a）的耗尽恢复了M114缺失ESC从幼稚多能性转变为引发多能性的能力。因此，我们定义了一个相反的调节轴，其中Lsd 1和相关的辅阻遏物直接抑制M114激活的基因靶。这一发现对人类发育综合征和携带M114突变的肿瘤的治疗具有广泛的意义。
The counterbalance between coactivator and co-repressor complexes at enhancers instructs stem cell pluripotency transition. Chromatin regulators control cellular differentiation by orchestrating dynamic developmental gene expression programs, and hence, malfunctions in the regulation of chromatin state contribute to both developmental disorders and disease state. Mll4 (Kmt2d), a member of the COMPASS (COMplex of Proteins ASsociated with Set1) protein family that implements histone H3 lysine 4 monomethylation (H3K4me1) at enhancers, is essential for embryonic development and functions as a pancancer tumor suppressor. We define the roles of Mll4/COMPASS and its catalytic activity in the maintenance and exit of ground-state pluripotency in murine embryonic stem cells (ESCs). Mll4 is required for ESC to exit the naive pluripotent state; however, its intrinsic catalytic activity is dispensable for this process. The depletion of the H3K4 demethylase Lsd1 (Kdm1a) restores the ability of Mll4 null ESCs to transition from naive to primed pluripotency. Thus, we define an opposing regulatory axis, wherein Lsd1 and associated co-repressors directly repress Mll4-activated gene targets. This finding has broad reaching implications for human developmental syndromes and the treatment of tumors carrying Mll4 mutations.
登录
查看更多内容
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
16.8
作者：
Hu D;Garruss AS;Gao X;Morgan MA;Cook M;Smith ER;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
64.8
作者：
Brons, I. Gabrielle M.;Smithers, Lucy E.;Vallier, Ludovic
通讯作者：
Vallier, Ludovic
影响因子：
4.6
作者：
Bledau, Anita S.;Schmidt, Kerstin;Anastassiadis, Konstantinos
通讯作者：
Anastassiadis, Konstantinos
影响因子：
16
作者：
Hu D;Gao X;Cao K;Morgan MA;Mas G;Smith ER;Volk AG;Bartom ET;Crispino JD;Di Croce L;Shilatifard A
通讯作者：
Shilatifard A