美国犹他大学医学院Bradley R. Cairns团队在研究中取得进展。他们发现p53可激活胚胎干细胞和面肩肱型肌营养不良细胞模型中的双同源盒(DUX)/DUX4。该项研究成果发表在2021年7月15日出版的《自然-遗传学》上。

研究人员发现p53-DUX/DUX4调节通路在人类中也是保守的。此外，研究发现在面肩肱型肌营养不良症(FSHD)患者来源的细胞中，p53通过灵长类特异的亚端粒长末端重复(LTR)10C元件中的p53结合位点激活人DUX4。总之，该研究工作表明p53激活将胚胎干细胞中p53与Dux/DUX4激活、胚胎和来自FSHD患者细胞中的Dux/DUX4激活结合起来，这可能将疾病的进展与DUX家族因子的调控结合起来，并提供了治疗FSHD的可能靶点。

研究人员表示，在哺乳动物胚胎中，适宜的胚胎基因组激活 (ZGA) 是其全面发育的基础。DUX家族因子参与调控ZGA，并且小鼠Dux是体外培养时双细胞(2C)样细胞形成所必需的。特别是在小鼠胚胎干细胞中，Dux被肿瘤抑制因子p53激活，并且Dux表达促进细胞分化为多种细胞类型。小鼠Dux基因座的长读长测序和组装揭示了其复杂的染色质调节，包括假定的正反馈和负反馈回路。

附：英文原文

Title: p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models

Author: Edward J. Grow, Bradley D. Weaver, Christina M. Smith, Jingtao Guo, Paula Stein, Sean C. Shadle, Peter G. Hendrickson, Nicholas E. Johnson, Russell J. Butterfield, Roberta Menafra, Susan L. Kloet, Silvre M. van der Maarel, Carmen J. Williams, Bradley R. Cairns

Issue&Volume: 2021-07-15

Abstract: In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53–DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD.

DOI: 10.1038/s41588-021-00893-0

Source: https://www.nature.com/articles/s41588-021-00893-0