UTX condensation underlies its tumour-suppressive activity.
UTX condensation underlies its tumour-suppressive activity.
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UTX缩合是其肿瘤抑制活性的基础。
DOI：
10.1038/s41586-021-03903-7
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发表时间：
2021-09
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
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作者：
UTX/KDM 6A编码组蛋白H3 K27去甲基化酶，并且是在人类癌症中经常突变的重要肿瘤抑制因子。然而，由于UTX的脱甲基酶活性在介导肿瘤抑制和发育调节中通常是不稳定的，因此UTX的潜在分子活性仍然是难以捉摸的。在这里，我们表明UTX的相分离是其在肿瘤抑制中的染色质调节活性的基础。UTX的核心固有无序区（cIDR）形成相分离的液体冷凝物，并且由UTX的最常见的癌症突变引起的cIDR损失主要负责消除肿瘤抑制。IDR缺失、诱变和置换试验证明UTX浓缩在肿瘤抑制和胚胎干细胞分化中的关键作用。如体外重建和细胞中的工程化系统所示，UTX将MLL 4/KMT 2D募集到相同的缩合物中并富集MLL 4的H3 K4甲基化活性。此外，UTX调节全基因组的组蛋白修饰和高阶染色质相互作用的浓缩依赖性的方式。我们还发现UTY，UTX的Y染色体同源物，具有较弱的肿瘤抑制活性，形成分子动力学降低的凝聚物。这些研究证明了具有适当物质状态的液体冷凝物在使染色质调节剂具有肿瘤抑制活性方面的关键生物学功能。
UTX/KDM6A encodes a histone H3K27 demethylase and is an important tumor suppressor frequently mutated in human cancers. However, as the demethylase activity of UTX is often dispensable in mediating tumor suppression and developmental regulation, the underlying molecular activity of UTX remains elusive. Here we show that phase separation of UTX underlies its chromatin regulatory activity in tumor suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumor suppression. IDR deletion, mutagenesis, and replacement assays demonstrate a critical role of UTX condensation in tumor suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits MLL4/KMT2D into the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homolog of UTX with weaker tumor-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumor suppressive activity of a chromatin regulator.