A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.
A proteomics study identifying interactors of the FSHD2 gene product SMCHD1 reveals RUVBL1-dependent DUX4 repression.
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DOI：
10.1038/s41598-021-03030-3
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发表时间：
2021-12-08
影响因子：
4.6
通讯作者：
van der Maarel SM
中科院分区：
文献类型：
--
作者：
Goossens R;Tihaya MS;van den Heuvel A;Tabot-Ndip K;Willemsen IM;Tapscott SJ;González-Prieto R;Chang JG;Vertegaal ACO;Balog J;van der Maarel SM
Smchd1是一种染色质抑制基因，在 >； 95%的面肩肩关节营养不良(FSHD)2型患者中发生突变。在FSHD2中，Smchd1突变最终导致肌肉细胞中存在解理阶段的转录因子DUX4，这是因为4Q染色体上包含DUX4基因的D4Z4大卫星重复序列的表观遗传抑制失败。虽然Smchd1与D4Z4的结合以及它在体细胞中维持抑制D4Z4染色质结构的必要性已经被很好地记录下来，但Smchd1是如何被招募到D4Z4上的，以及它是如何对染色质发挥抑制作用的还不清楚。在这里，我们使用定量蛋白质组学的方法来识别和表征新的Smchd1相互作用蛋白，并评估它们在D4Z4抑制中的功能。我们鉴定了28个Smchd1核相互作用蛋白，其中12个存在于心肌细胞的D4Z4染色质中。我们证明，这些Smchd1相互作用蛋白之一RuvB-like 1(RUVBL1)的缺失，进一步降低了FSHD心肌细胞中DUX4的表达。我们还证实了Smchd1与EZH抑制蛋白(EZHIP)的相互作用，EZHIP是一种通过多梳抑制复合体PRC2防止H3K27me3全局沉积的蛋白质，为Smchd1在胚胎发育早期抑制DUX4的潜在功能提供了新的见解。因此，本文概述的Smchd1相互作用体可以为进一步研究Smchd1在基因组中已知作用的基因座上的潜在功能提供方向，例如D4Z4重复、非活跃的X染色体、常染色体簇、印迹基因座和端粒。
Structural Maintenance of Chromosomes Hinge Domain Containing 1 (SMCHD1) is a chromatin repressor, which is mutated in > 95% of Facioscapulohumeral dystrophy (FSHD) type 2 cases. In FSHD2, SMCHD1 mutations ultimately result in the presence of the cleavage stage transcription factor DUX4 in muscle cells due to a failure in epigenetic repression of the D4Z4 macrosatellite repeat on chromosome 4q, which contains the DUX4 locus. While binding of SMCHD1 to D4Z4 and its necessity to maintain a repressive D4Z4 chromatin structure in somatic cells are well documented, it is unclear how SMCHD1 is recruited to D4Z4, and how it exerts its repressive properties on chromatin. Here, we employ a quantitative proteomics approach to identify and characterize novel SMCHD1 interacting proteins, and assess their functionality in D4Z4 repression. We identify 28 robust SMCHD1 nuclear interactors, of which 12 are present in D4Z4 chromatin of myocytes. We demonstrate that loss of one of these SMCHD1 interacting proteins, RuvB-like 1 (RUVBL1), further derepresses DUX4 in FSHD myocytes. We also confirm the interaction of SMCHD1 with EZH inhibitory protein (EZHIP), a protein which prevents global H3K27me3 deposition by the Polycomb repressive complex PRC2, providing novel insights into the potential function of SMCHD1 in the repression of DUX4 in the early stages of embryogenesis. The SMCHD1 interactome outlined herein can thus provide further direction into research on the potential function of SMCHD1 at genomic loci where SMCHD1 is known to act, such as D4Z4 repeats, the inactive X chromosome, autosomal gene clusters, imprinted loci and telomeres.
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影响因子：
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作者：
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通讯作者：
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