Tomaz Rute A, Harman Jennifer L, Karimlou Donja, Weavers Lauren, Fritsch Lauriane, Bou-Kheir Tony, Bell Emma, Del Valle Torres Ignacio, Niakan Kathy K, Fisher Cynthia, Joshi Onkar, Stunnenberg Hendrik G, Curry Edward, Ait-Si-Ali Slimane, Jørgensen Helle F, Azuara Véronique
Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London W12 0NN, UK.
Cardiovascular Medicine Division, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
Development. 2017 Feb 15;144(4):567-579. doi: 10.1242/dev.142489. Epub 2017 Jan 13.
Jmjd2 H3K9 demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we reveal that Jmjd2c facilitates this process by stabilising the assembly of mediator-cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, while -knockout ESCs remain capable of forming extra-embryonic endoderm derivatives. Dissection of the underlying molecular basis revealed that Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming for differentiation. Interestingly, Jmjd2c-bound enhancers are co-occupied by the H3K9-methyltransferase G9a (also known as Ehmt2), independently of its H3K9-modifying activity. Loss of Jmjd2c abrogates G9a recruitment and further destabilises loading of the mediator and cohesin components Med1 and Smc1a at newly activated and poised enhancers in ESC-derived epiblast-like cells. These findings unveil Jmjd2c and G9a as novel enhancer-associated factors, and implicate Jmjd2c as a molecular scaffold for the assembly of essential enhancer-protein complexes with an impact on timely gene activation.
Jmjd2 H3K9去甲基化酶协同促进小鼠胚胎干细胞（ESC）特性。然而，对于它们在ESC多能性退出时的重要性却知之甚少。在此，我们揭示Jmjd2c通过稳定谱系特异性增强子处中介体-黏连蛋白复合物的组装来促进这一过程。在功能上，我们表明ESC中需要Jmjd2c来在体细胞多谱系分化时启动适当的基因表达程序。在没有Jmjd2c的情况下，分化在植入后早期类上胚层阶段停滞，而敲除Jmjd2c的ESC仍能够形成胚外内胚层衍生物。对潜在分子基础的剖析表明，在ESC启动分化过程中，Jmjd2c重新分布到谱系特异性增强子。有趣的是，与Jmjd2c结合的增强子被H3K9甲基转移酶G9a（也称为Ehmt2）共同占据，与其H3K9修饰活性无关。Jmjd2c的缺失消除了G9a的募集，并进一步破坏了中介体和黏连蛋白成分Med1和Smc1a在ESC来源的类上胚层细胞中新激活和准备就绪的增强子处的装载。这些发现揭示Jmjd2c和G9a是新型的增强子相关因子，并表明Jmjd2c作为组装对及时基因激活有影响的必需增强子-蛋白质复合物的分子支架。
