Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states.
Dynamics of BAF-Polycomb complex opposition on heterochromatin in normal and oncogenic states.
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DOI：
10.1038/ng.3734
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发表时间：
2017-02
期刊：
影响因子：
30.8
通讯作者：
Crabtree GR
中科院分区：
文献类型：
--
作者：
Kadoch C;Williams RT;Calarco JP;Miller EL;Weber CM;Braun SM;Pulice JL;Chory EJ;Crabtree GR
多梳抑制复合物（PRC）和BAF （mSWI/SNF）复合物之间的对立在发育和疾病中起着关键作用。编码BAF亚基的基因突变导致了超过20%的人类恶性肿瘤，但其潜在机制尚不清楚，主要原因是缺乏评估BAF在体内功能的检测方法。为了解决这个问题，我们开发了一种广泛适用的招募分析系统，并发现BAF通过快速的atp依赖性排出来对抗PRC，从而导致可接近染色质的形成。逆转这一过程导致兼性异染色质的重组。令人惊讶的是，baf介导的PRC驱逐发生在没有PolII占用、转录和复制的情况下。此外，我们发现肿瘤抑制因子和致癌因子BAF复合物突变对PRC驱逐的影响不同。这些研究确定了兼性异染色质分解和形成的机制序列，并证明BAF在每分钟的基础上反对多梳复合物，以提供表观遗传可塑性。
The opposition between polycomb repressive complexes (PRC) and BAF (mSWI/SNF) complexes plays critical roles in development and disease. Mutations in the genes encoding BAF subunits contribute to over 20% of human malignancy, yet the underlying mechanisms remain unclear owing largely to a lack of assays to assess BAF function in vivo. To address this, we have developed a widely applicable recruitment assay system and find that BAF opposes PRC by rapid, ATP-dependent eviction, leading to the formation of accessible chromatin. Reversing this process results in reassembly of facultative heterochromatin. Surprisingly, BAF-mediated PRC eviction occurs in the absence of PolII occupancy, transcription, and replication. Further, we find that tumor suppressor and oncogenic BAF complex mutations result in differential effects on PRC eviction. These studies define a mechanistic sequence underlying the resolution and formation of facultative heterochromatin and demonstrate that BAF opposes polycomb complexes on a minute-by-minute basis to provide epigenetic plasticity.