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.

中文翻译：

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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

DUX4 转录因子由嵌入在 D4Z4 大卫星重复序列每个单元中的逆转录基因编码。DUX4 通常在卵裂期胚胎中表达，而染色质抑制阻止了 DUX4 在大多数体细胞组织中的表达。由于 DUX4 在骨骼肌中的错误表达，这种抑制的失败会导致面肩肱型肌营养不良症 (FSHD)。在本研究中，我们使用 CRISPR/Cas9 工程染色质免疫沉淀 (enChIP) 位点特异性蛋白质组学来表征 D4Z4 相关蛋白。这些方法和其他方法确定了核小体重塑脱乙酰酶 (NuRD) 和染色质组装因子 1 (CAF-1) 复合物是人类骨骼肌细胞和诱导多能干 (iPS) 细胞中 DUX4 抑制所必需的。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，这些发现将 NuRD 和 CAF-1 鉴定为 DUX4 染色质抑制的介质，并提出了 FSHD 肌肉细胞中 DUX4 表达放大的机制。