小柯机器人

美国哈佛医学院Cigall Kadoch团队近期通过研究SMARCB1突变揭示出一个核小体酸性模块相互作用位点，其能够促进mSWI/SNF复合物进行染色质重塑。 相关论文2019年11月20日在线发表于《细胞》。

研究人员报道了SMARCB1亚基CTD结构域高频出现的单氨基酸突变（BAF47）在分子、结构和全基因组范围调控的相关影响，该突变会导致智力残疾紊乱Coffin-Siris综合征（CSS），并且经常在癌症中发现。研究人员发现，SMARCB1 CTD包含一个直接与核小体酸性模块直接结合的碱性α螺旋，并且所有与CSS相关的突变都破坏了这种结合。此外，这些突变消除了mSWI / SNF介导的核小体重塑活性和增强子DNA可及性，而不会改变全基因组范围内的复合物定位。最后，杂合CSS相关的SMARCB1突变导致iPSC神经元分化过程中的主要基因调节和形态变化。这些研究揭示了在人类疾病中改变的SMARCB1 CTD在进化上保守的结构作用。

据了解，mSWI/SNF（mammalian switch/sucrose non-fermentable）复合物是重塑染色质结构的多组分机器。拆分亚基和特定结构域对复合物活性的贡献能够促进对背后机制的理解。

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