TY - JOUR
T1 - p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models
AU - Grow, Edward J.
AU - Weaver, Bradley D.
AU - Smith, Christina M.
AU - Guo, Jingtao
AU - Stein, Paula
AU - Shadle, Sean C.
AU - Hendrickson, Peter G.
AU - Johnson, Nicholas E.
AU - Butterfield, Russell J.
AU - Menafra, Roberta
AU - Kloet, Susan L.
AU - van der Maarel, Silvère M.
AU - Williams, Carmen J.
AU - Cairns, Bradley R.
N1 - Funding Information:
Oliver for the Trp53fl/fl mouse, S.J. Tapscott for FSHD1 and FSHD2 myoblasts, F. Zhang for the px330-Cas9 plasmid, S. Jackson for the pICE-HA-NLS-I-PpoI plasmid, A. Chavez and G. Church for the dCas9-KRAB-MeCP2 plasmid and C. Gersbach for the pcDNA-dCas9-p300(HAT) plasmid. We also thank B. Dalley in the HCI High-Throughput Genomics and Bioinformatic Analysis Shared Resource (NCI grant P30CA042014), the CCTS Stem Cell Facility (National Institutes of Health (NIH), UL1TR002538), J. Marvin and the University of Utah Flow Cytometry Facility (NIH, 1S10RR026802-01; NCI, 5P30CA042014-24) and the University of Utah Cell Imaging Core. Funding for this work supported C.J.W. in part from the Intramural Research Program of the NIH (NIEHS, 1ZIAES102985), the NCI (P30 CA015704-45S6) and W.OP.14-01 from the Prinses Beatrix Spierfonds to S.M.v.d.M., and additional funding was from Wellstone Center from UMass (NICHD, P50HD060848) to R.J.B., the NIH (F30HD098000) to B.D.W., the NICHD (F32HD104442) to S.C.S., the NICHD (F32HD094500) and Lalor Foundation Fellowship 10041116 to E.J.G. and the Howard Hughes Medical Institute and the NICHD (1R01HD095833) to B.R.C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
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U2 - 10.1038/s41588-021-00893-0
DO - 10.1038/s41588-021-00893-0
M3 - Article
C2 - 34267371
AN - SCOPUS:85110700036
SN - 1061-4036
VL - 53
SP - 1207
EP - 1220
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -