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NuRD 和 CAF-1 介导的 D4Z4 阵列沉默受 DUX4 诱导的 MBD3L 蛋白调节。

NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins.

机构信息

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, United States.

Molecular and Cellular Biology Program, University of Washington, Seattle, United States.

出版信息

Elife. 2018 Mar 13;7:e31023. doi: 10.7554/eLife.31023.

DOI:10.7554/eLife.31023
PMID:29533181
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5849414/
Abstract

The DUX4 transcription factor is encoded by a retrogene embedded in each unit of the D4Z4 macrosatellite repeat. DUX4 is normally expressed in the cleavage-stage embryo, whereas chromatin repression prevents DUX4 expression in most somatic tissues. Failure of this repression causes facioscapulohumeral muscular dystrophy (FSHD) due to mis-expression of DUX4 in skeletal muscle. In this study, we used CRISPR/Cas9 engineered chromatin immunoprecipitation (enChIP) locus-specific proteomics to characterize D4Z4-associated proteins. These and other approaches identified the Nucleosome Remodeling Deacetylase (NuRD) and Chromatin Assembly Factor 1 (CAF-1) complexes as necessary for DUX4 repression in human skeletal muscle cells and induced pluripotent stem (iPS) cells. Furthermore, DUX4-induced expression of MBD3L proteins partly relieved this repression in FSHD muscle cells. Together, these findings identify NuRD and CAF-1 as mediators of DUX4 chromatin repression and suggest a mechanism for the amplification of DUX4 expression in FSHD muscle cells.

摘要

DUX4 转录因子由嵌入 D4Z4 大片段重复单位的反转录基因编码。DUX4 在胚胎的卵裂期正常表达，而染色质抑制阻止 DUX4 在大多数体细胞组织中的表达。由于 DUX4 在骨骼肌中的异常表达，这种抑制的失败导致面肩肱型肌营养不良症（FSHD）。在这项研究中，我们使用 CRISPR/Cas9 工程化的染色质免疫沉淀（enChIP）基因座特异性蛋白质组学来表征与 D4Z4 相关的蛋白质。这些和其他方法鉴定了核小体重塑去乙酰化酶（NuRD）和染色质组装因子 1（CAF-1）复合物是在人类骨骼肌细胞和诱导多能干细胞（iPS 细胞）中抑制 DUX4 所必需的。此外，DUX4 诱导的 MBD3L 蛋白表达部分缓解了 FSHD 肌肉细胞中的这种抑制。总之，这些发现确定了 NuRD 和 CAF-1 是 DUX4 染色质抑制的介质，并提出了 FSHD 肌肉细胞中 DUX4 表达扩增的机制。

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