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

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, Silvère M. van der Maarel, Carmen J. Williams, Bradley R. Cairns

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1207-1220
Number of pages14
JournalNature genetics
Volume53
Issue number8
DOIs
StatePublished - Aug 2021
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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