MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis.
MED12 Regulates HSC-Specific Enhancers Independently of Mediator Kinase Activity to Control Hematopoiesis.
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MED12独立于介质激酶活性来控制HSC特异性增强剂以控制造血。
DOI：
10.1016/j.stem.2016.08.004
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发表时间：
2016-12-01
期刊：
影响因子：
23.9
通讯作者：
Aifantis I
中科院分区：
文献类型：
--
作者：
Aranda-Orgilles B;Saldaña-Meyer R;Wang E;Trompouki E;Fassl A;Lau S;Mullenders J;Rocha PP;Raviram R;Guillamot M;Sánchez-Díaz M;Wang K;Kayembe C;Zhang N;Amoasii L;Choudhuri A;Skok JA;Schober M;Reinberg D;Sicinski P;Schrewe H;Tsirigos A;Zon LI;Aifantis I
造血特异性转录因子需要辅激活子与一般转录机制通信并建立维持造血干细胞（HSC）自我更新、促进分化和防止恶性转化的转录程序。Mediator是一个大的辅激活因子复合物，它将增强子定位的转录因子与启动子连接起来，但对Mediator在成体干细胞自我更新和分化中的功能知之甚少。我们表明，MED12，一个成员的中介激酶模块，是一个重要的调节HSC的稳态，在体内删除Med12导致快速骨髓再生障碍性贫血，导致急性致死性。删除介体激酶模块的其他成员不影响HSC功能，表明MED12的激酶独立作用。MED12缺失使P300在谱系特异性增强子处的结合不稳定，导致H3K27Ac耗尽、增强子失活以及随后的HSC干性特征的丧失。由于最近在血液恶性肿瘤中描述了MED12突变，MED12依赖性增强子调节的改变可能控制生理和恶性造血。
Hematopoietic-specific transcription factors require coactivators to communicate with the general transcription machinery and establish transcriptional programs that maintain hematopoietic stem cell (HSC) self-renewal, promote differentiation, and prevent malignant transformation. Mediator is a large coactivator complex that bridges enhancer-localized transcription factors with promoters, but little is known about Mediator function in adult stem cell self-renewal and differentiation. We show that MED12, a member of the Mediator kinase module, is an essential regulator of HSC homeostasis, as in vivo deletion of Med12 causes rapid bone marrow aplasia leading to acute lethality. Deleting other members of the Mediator kinase module does not affect HSC function, suggesting kinase-independent roles of MED12. MED12 deletion destabilizes P300 binding at lineage-specific enhancers, resulting in H3K27Ac depletion, enhancer de-activation, and consequent loss of HSC stemness signatures. As MED12 mutations have been described recently in blood malignancies, alterations in MED12-dependent enhancer regulation may control both physiological and malignant hematopoiesis.