SMARCB1突變影響mSWI/SNF複合物介導的染色質重塑
作者：
小柯機器人發布時間：2019/11/21 13:06:20
美國哈佛醫學院Cigall Kadoch團隊近期通過研究SMARCB1突變揭示出一個核小體酸性模塊相互作用位點，其能夠促進mSWI/SNF複合物進行染色質重塑。 相關論文2019年11月20日在線發表於《細胞》。
研究人員報導了SMARCB1亞基CTD結構域高頻出現的單胺基酸突變（BAF47）在分子、結構和全基因組範圍調控的相關影響，該突變會導致智力殘疾紊亂Coffin-Siris症候群（CSS），並且經常在癌症中發現。研究人員發現，SMARCB1 CTD包含一個直接與核小體酸性模塊直接結合的鹼性α螺旋，並且所有與CSS相關的突變都破壞了這種結合。此外，這些突變消除了mSWI / SNF介導的核小體重塑活性和增強子DNA可及性，而不會改變全基因組範圍內的複合物定位。最後，雜合CSS相關的SMARCB1突變導致iPSC神經元分化過程中的主要基因調節和形態變化。這些研究揭示了在人類疾病中改變的SMARCB1 CTD在進化上保守的結構作用。
據了解，mSWI/SNF（mammalian switch/sucrose non-fermentable）複合物是重塑染色質結構的多組分機器。拆分亞基和特定結構域對複合物活性的貢獻能夠促進對背後機制的理解。
附：英文原文
Title: Recurrent SMARCB1 Mutations Reveal a Nucleosome Acidic Patch Interaction Site That Potentiates mSWI/SNF Complex Chromatin Remodeling
Author: Alfredo M. Valencia, Clayton K. Collings, Hai T. Dao, Roodolph St. Pierre, Yung-Chih Cheng, Junwei Huang, Zhen-Yu Sun, Hyuk-Soo Seo, Nazar Mashtalir, Dawn E. Comstock, Olubusayo Bolonduro, Nicholas E. Vangos, Zoe C. Yeoh, Mary Kate Dornon, Crystal Hermawan, Lee Barrett, Sirano Dhe-Paganon, Clifford J. Woolf, Tom W. Muir, Cigall Kadoch
Issue&Volume: November 20, 2019
Abstract: Mammalian switch/sucrose non-fermentable (mSWI/SNF) complexes are multi-componentmachines that remodel chromatin architecture. Dissection of the subunit- and domain-specificcontributions to complex activities is needed to advance mechanistic understanding.Here, we examine the molecular, structural, and genome-wide regulatory consequencesof recurrent, single-residue mutations in the putative coiled-coil C-terminal domain(CTD) of the SMARCB1 (BAF47) subunit, which cause the intellectual disability disorderCoffin-Siris syndrome (CSS), and are recurrently found in cancers. We find that theSMARCB1 CTD contains a basic α helix that binds directly to the nucleosome acidicpatch and that all CSS-associated mutations disrupt this binding. Furthermore, thesemutations abrogate mSWI/SNF-mediated nucleosome remodeling activity and enhancer DNAaccessibility without changes in genome-wide complex localization. Finally, heterozygousCSS-associated SMARCB1 mutations result in dominant gene regulatory and morphologic changes during iPSC-neuronaldifferentiation. These studies unmask an evolutionarily conserved structural rolefor the SMARCB1 CTD that is perturbed in human disease.
DOI: 10.1016/j.cell.2019.10.044
Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31221-8
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