Increased ACTL6A occupancy within mSWI/SNF chromatin remodelers drives human squamous cell carcinoma.
Increased ACTL6A occupancy within mSWI/SNF chromatin remodelers drives human squamous cell carcinoma.
复制标题
mSWI/SNF染色质重塑中增加的ACTL 6A占据驱动人鳞状细胞癌。
DOI：
10.1016/j.molcel.2021.10.005
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发表时间：
2021-12-16
期刊：
影响因子：
16
通讯作者：
Crabtree GR
中科院分区：
文献类型：
--
作者：
Chang CY;Shipony Z;Lin SG;Kuo A;Xiong X;Loh KM;Greenleaf WJ;Crabtree GR
哺乳动物SWI/SNF（BAF）染色质重塑在许多人类恶性肿瘤和神经系统疾病中起剂量敏感作用。编码BAF亚单位ACTL 6A的基因在许多鳞状细胞癌（SCC）的发展早期扩增，但其致癌作用仍不清楚。在这里，我们证明，ACTL 6A过表达导致其化学计量组装成BAF复合物，并驱动它们的相互作用和参与与基因组中的特定调控区域。在正常上皮细胞中，ACTL 6A是其他BAF亚基的亚化学计量。然而，通过异位表达或在SCC细胞中增加的ACTL 6A水平导致BAF复合物内ACTL 6A接近饱和。增加ACTL 6A占据增强了全基因组的多梳对立以激活SCC基因，并且还促进了BAF和TEAD-YAP复合物在染色质上的共依赖性加载。这两种机制似乎都是关键的，并作为SCC启动和维持的分子与门，从而解释了SCC中ACTL 6A扩增作用的特异性。Chang等人发现ACTL 6A在鳞状细胞癌（SCC）中起剂量敏感性作用。在SCC发展过程的早期，ACTL 6A基因扩增增加了其在BAF复合物内的正常不饱和占据，导致通过PRC再分布和TEAD-YAP的染色质负载增加的表观遗传去抑制。
Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF-subunit, ACTL6A, is amplified early in the development of many squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives their interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was substoichiometric to other BAF-subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes. Increased ACTL6A occupancy enhanced polycomb opposition genome-wide to activate SCC genes, and also facilitated the co-dependent loading of BAF and TEAD-YAP complexes on chromatin. Both mechanisms appeared to be critical and function as a molecular AND gate for SCC initiation and maintenance, thereby explaining the specificity of the role of ACTL6A amplification in SCCs. Chang et al. find ACTL6A plays a dosage-sensitive role underlying squamous cell carcinoma (SCC). Early in the course of the development of SCC, ACTL6A gene amplification increases its normally unsaturated occupancy within BAF complexes, leading to epigenetic de-repression by PRC redistribution and increased chromatin loading of TEAD-YAP.
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影响因子：
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作者：
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