Human DUX4 and porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD.
Human DUX4 and porcine DUXC activate similar early embryonic programs in pig muscle cells: implications for preclinical models of FSHD.
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人 DUX4 和猪 DUXC 激活猪肌肉细胞中类似的早期胚胎程序：对 FSHD 临床前模型的影响。
DOI：
10.1093/hmg/ddad021
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发表时间：
2023
影响因子：
3.5
通讯作者：
Tapscott,StephenJ
中科院分区：
文献类型：
--
作者：
Nip,Yee;Bennett,SeanR;Smith,AndrewA;Jones,TakakoI;Jones,PeterL;Tapscott,StephenJ
人DUX4及其小鼠直系同源物Dux通常分别在早期胚胎（4细胞或2细胞卵裂期胚胎）中表达，并激活合子基因表达第一波的一部分。DUX4在几乎所有的体细胞组织中都受到表观遗传学抑制，而引起面肩肱营养不良（FSHD）的突变导致其在骨骼肌中的异常表达，早期胚胎程序的转录激活和随后的肌肉病理学。虽然DUX4和Dux都激活了早期全能转录程序，但它们的DNA结合结构域的差异限制了小鼠中表达的DUX4作为FSHD的临床前模型的使用。在这项研究中，我们鉴定了在早期发育中表达的猪DUXC信使核糖核酸，并表明猪DUXC和人DUX4在猪肌肉细胞中强烈激活了高度相似的早期胚胎程序。这些结果支持进一步研究FSHD的猪临床前模型。
Human DUX4 and its mouse ortholog Dux are normally expressed in the early embryo—the 4-cell or 2-cell cleavage stage embryo, respectively—and activate a portion of the first wave of zygotic gene expression. DUX4 is epigenetically suppressed in nearly all somatic tissue, whereas facioscapulohumeral dystrophy (FSHD)-causing mutations result in its aberrant expression in skeletal muscle, transcriptional activation of the early embryonic program and subsequent muscle pathology. Although DUX4 and Dux both activate an early totipotent transcriptional program, divergence of their DNA binding domains limits the use of DUX4 expressed in mice as a preclinical model for FSHD. In this study, we identify the porcine DUXC messenger ribonucleic acid expressed in early development and show that both pig DUXC and human DUX4 robustly activate a highly similar early embryonic program in pig muscle cells. These results support further investigation of pig preclinical models for FSHD.