Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription.
Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription.
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DOI：
10.1016/j.celrep.2021.109943
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发表时间：
2021-11-02
期刊：
影响因子：
8.8
通讯作者：
Owen-Hughes T
中科院分区：
文献类型：
--
作者：
Blümli S;Wiechens N;Wu MY;Singh V;Gierlinski M;Schweikert G;Gilbert N;Naughton C;Sundaramoorthy R;Varghese J;Gourlay R;Soares R;Clark D;Owen-Hughes T
SWI/SNF染色质重塑复合物的ARID 1A亚基是一种有效的肿瘤抑制因子。在这里，降解决定子被应用于检测数千个基因座处的染色质可及性的快速丧失，在这些基因座中ARID 1A起作用以产生核小体的可及性微域。ARID 1A的缺失也导致共活化剂EP 300的再分布。同时发生的EP 300解离和增强子元件处的染色质可及性丧失在快速下调的基因附近高度富集。相反，获得的EP 300占据位点与转录上调的基因相关。这些染色质变化与ARID 1A丢失后最初几个小时内差异表达的少量基因相关。间接或适应性变化在ARID 1A缺失后的生长后数天内主导转录组，并导致与癌症途径的强烈参与。这种层次结构的识别表明，在ARID 1A驱动的疾病的干预网站。ARID 1A的降解破坏了多能性转录因子EP 300侧翼的核小体，并在上调基因附近迅速重新分布，占据率增加。这些变化与2小时内数百个基因的误调节有关。显示ARID 1A降解重组多能性转录因子侧翼的核小体并引起共激活因子EP 300的再分布。在增强子处丢失的EP 300与转录的下调相关，并且随着上调而获得EP 300。很少有基因受到直接影响，但广泛的间接影响积累缓慢表型癌前病变。
The ARID1A subunit of SWI/SNF chromatin remodeling complexes is a potent tumor suppressor. Here, a degron is applied to detect rapid loss of chromatin accessibility at thousands of loci where ARID1A acts to generate accessible minidomains of nucleosomes. Loss of ARID1A also results in the redistribution of the coactivator EP300. Co-incident EP300 dissociation and lost chromatin accessibility at enhancer elements are highly enriched adjacent to rapidly downregulated genes. In contrast, sites of gained EP300 occupancy are linked to genes that are transcriptionally upregulated. These chromatin changes are associated with a small number of genes that are differentially expressed in the first hours following loss of ARID1A. Indirect or adaptive changes dominate the transcriptome following growth for days after loss of ARID1A and result in strong engagement with cancer pathways. The identification of this hierarchy suggests sites for intervention in ARID1A-driven diseases. Degradation of ARID1A disrupts nucleosomes flanking pluripotency transcription factors EP300 is rapidly redistributed with increased occupancy adjacent to upregulated genes These changes are associated with misregulation of a few hundred genes within 2 h During subsequent days, widespread indirect changes mimic a premalignant state Blümli et al. show that degradation of ARID1A reorganizes nucleosomes flanking pluripotency transcription factors and causes redistribution of the coactivator EP300. Lost EP300 at enhancers is associated with downregulation of transcription and gained EP300 with upregulation. Few genes are directly affected, but widespread indirect effects accumulate slowly to phenocopy premalignancy.
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影响因子：
23.9
作者：
Brookes, Emily;de Santiago, Ines;Hebenstreit, Daniel;Morris, Kelly J.;Carroll, Tom;Xie, Sheila Q.;Stock, Julie K.;Heidemann, Martin;Eick, Dirk;Nozaki, Naohito;Kimura, Hiroshi;Ragoussis, Jiannis;Teichmann, Sarah A.;Pombo, Ana
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作者：
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影响因子：
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