Porcine DUXC and human DUX4 activate similar embryonic programs cross species: implications for preclinical model of FSHD. Porcine DUXC and human DUX4 activate similar embryonic programs cross species: implications for preclinical model of FSHD

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 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 pre-clinical model for FSHD. In this study, we identify the porcine DUXC mRNA 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. Overall design: Overexpression of human DUX4, pig DUXC, or GFP control in primary pig myoblasts.

DUX4及其小鼠直系同源基因Dux通常分别在4细胞卵裂期胚胎与2细胞卵裂期胚胎中表达，并激活合子基因表达第一波转录程序的一部分。DUX4在几乎所有体细胞组织中均受表观遗传抑制，而导致面肩肱型肌营养不良症（FSHD）的突变会使其在骨骼肌中异常表达，引发早期胚胎程序的转录激活以及后续的肌肉病理改变。尽管DUX4与Dux均可激活早期全能性转录程序，但二者的DNA结合结构域存在序列差异，这限制了在小鼠中表达的DUX4作为FSHD临床前模型的应用。本研究鉴定了早期发育过程中表达的猪源DUXC mRNA，并证实猪DUXC与人类DUX4均可在猪肌细胞中高效激活高度相似的早期胚胎转录程序。上述结果支持对FSHD的猪临床前模型开展进一步研究。总体实验设计：在猪原代成肌细胞中过表达人源DUX4、猪源DUXC或绿色荧光蛋白（GFP）对照。