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.
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Data availability
All data, cell lines, reagents and unique materials are available upon request. ChIP–seq, ATAC-seq, scRNA-seq and RNA-seq data were deposited under GSE149267 and are detailed in Supplementary Table 4. Source data are provided with this paper.
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Acknowledgements
We thank members of the Cairns laboratory and M.B. Chandrasekharan for fruitful discussions. We are grateful to the patients who made this work possible. We thank T. 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.
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IRB processing, patient consent, patient management and sample selection and processing were overseen by N.E.J. and R.J.B. Experiments and analyses were conducted by E.J.G., B.D.W., C.M.S., J.G., S.C.S., P.G.H., P.S., R.M. and S.L.K. with contributions by C.J.W. and S.M.v.d.M. E.J.G. and B.R.C. designed the study and wrote the manuscript with input from co-authors.
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Extended data
Extended Data Fig. 1 Related to Fig. 1.
a, Dux expression in aphidicolin or vehicle control treatment of Trp53 WT mESC or Trp53 KO mESC. RT-qPCR, n = 3 biological replicates, * pvalue<0.05, for p53WT p-value = 0.02041, for p53KO p-value= p-value = 0.05449, t-test, one sided. b, Schematic of Dux locus in mm10 genome assembly, the design of the targeting construct, location of gRNAs for Dux KO mESC line generation. Shown below are locations of genotyping primers. c, RT-qPCR analysis Dux KO mESC clones #1 and #2 treated with doxorubicin to induce endogenous Dux expression, which were used for experiments in Fig. 1. Shown is a representative analysis of three independent experiments. d, Design of DUX peptide antigen for antibody creation. e, immunofluorescence with the rabbit polyclonal anti-DUX antibody using mESC with a tetracycline inducible DUX-3xHA transgene. Representative image from 3 independent experiments. Merge: DAPI = blue, DUX = red. Scale bar = 125 micrometers. f, Kinetic analysis of Dux and Zscan4 transcript induction in WT mESC treated with 1uM of doxorubicin for indicated times. Note earlier induction of Dux compared to Zscan4, the RNAseq from Fig1 and Fig2 is using the later time point 18H. FACS/flow cytometry gating scheme to exclude doublets. For Extended Data Fig 1a, the median is shown as a line in the box, and the outline of the box is depicted at the 25th and 75th percentile. The extended whiskers depict Q1-1.5*IQR and Q3 + 1.5*IQR. Outliers points are depicted as dots.
Extended Data Fig. 2 Related to Fig. 2.
a, Western blot analysis and KO deletion allele Sanger sequencing results for two independent Trp53 KO mESC clones (used for Fig. 2). b, RT-qPCR measure of Dux or Zscan4 expression levels in two independent Dppa2/4 dKO mESC clones. Dppa2/4 dKO clone #1 was used for Fig. 2e with p53 rescue experiments. *<0.05 FDR, One-way ANOVA. c, Western blot confirmation of dKO Dppa2/4 mESC clones #1, 2. d, Dux expression in Trp53 WT mESC after control or Trp53 siRNA knockdown, with vehicle or doxorubicin treatment. RT-qPCR, N = 6 biological replicates, *<0.05 FDR, One-way ANOVA. e, Co-overexpression of DPPA2/4 in Trp53 WT mESC does not activate Dux expression. Merge: DAPI = cyan, DPPA2 = yellow, DPPA4 = magenta. Representative image from 3 independent experiments. Scale bar = 125 micrometers. For Extended Data Fig 2b, d, the median is shown as a line in the box, and the outline of the box is depicted at the 25th and 75th percentile. The extended whiskers depict Q1-1.5*IQR and Q3 + 1.5*IQR. Outliers points are depicted as dots.
Extended Data Fig. 3 Related to Fig. 3.
a, Schematic of long-read (PacBio) sequenced and assembled mouse Dux locus. b, CRISPR-A experiment in Trp53 KO mESC. CRIPSR-A with the Dux promoter-targeted gRNAs strongly activates Dux expression. RT-qPCR, n = 3 biological replicates. c, Mouse Nelfa locus showing enrichment of DUX binding at the 3’ end of the gene at intronic MERVL element. Bottom panel is zoomed (n = 2 biological replicates for each condition). Barplot (middle panel) of doxycycline induced Dux transgenic mESC showing strong induction of Nelfa transcripts (RNA-seq, n = 2 biological replicates, * FDR < 0.05, DESeq2, data reprocessed from Hendrickson, et al. Nature Genetics 2017). Right-most panel: Metagene plot of the 28xDux repeat units showing p53-ChIP-seq and input control and NELFA ChIP-seq and input control (blue and black lines respectively from Hu, et al. Nature Cell Biology, 2020—note lower NELFA ChIP-seq signal compared to the matched-control input). d, Nelfa is transcriptionally induced by doxorubicin treatment, and this requires both p53 and DUX. RNA-seq from this paper, n = 2 biological replicates, * FDR < 0.05 DESeq2. e, Mdm2 and Krt5 are direct p53 targets. p53 ChIP-seq and H3K27ac ChIP-seq (n = 2 biological replicates). RT-qPCR measuring Mdm2 expression in control mESC or ZSCAN4-OE mESC, treated with vehicle control or doxorubicin; n = 5 biological replicates, *p-value <0.05, one-sides t-test. f, Immunofluorescence staining of control mESC (n = 135 cells) or clonal ZSCAN4-OE mESC (n = 487 cells) using phospho-p53 antibodies after doxorubicin treatment, n. *<0.001, one-sided Wilcox test. g, Brightfield image showing decreased cell death after doxorubicin treatment in ZSCAN4-OE mESC compared to control. Image is representative from 3 independent experiments. Scale bar = 125 micrometers. For Extended Data Fig 3e, f, the median is shown as a line in the box, and the outline of the box is depicted at the 25th and 75th percentile. The extended whiskers depict Q1-1.5*IQR and Q3 + 1.5*IQR. Outliers points are depicted as dots.
Extended Data Fig. 4 Related to Fig. 4.
a, Immunofluorescence of pronuclei (PN)-stage zygotes showing nuclear phospho-S15 p53 staining (quantified in Fig. 4a). Scale bar = 40 micrometers. b, Single mouse zygote RT-qPCR measuring Dux expression in PN5 stage zygotes (n = 7 p53 MZ-KO, n = 16 p53 WT), * p-value <0.05, p-value= 0.0409, one-sided t-test. For Extended Data Fig 4b, the median is shown as a line in the box, and the outline of the box is depicted at the 25th and 75th percentile. The extended whiskers depict Q1-1.5*IQR and Q3 + 1.5*IQR. Outliers points are depicted as dots.
Extended Data Fig. 5 Related to Fig. 5.
a, Comparison of two biological replicates for EB scRNAseq (control vs Dux-pulsed) showing high concordance between samples. b, Ibarra-Soria, et al. Nature Cell Biology ‘Defining murine organogenesis at single-cell resolution reveals a role for the leukotriene pathway in regulating blood progenitor formation’ depicting different cell types defined in E8.25 mouse embryos, (data retrieved from https://marionilab.cruk.cam.ac.uk/organogenesis/ February 2020). c, Analysis of Ibarra-Soria, et al. data compared to our EB scRNAseq data with indicated markers identifying cell types (see Fig. 4c table). Each plot shows the marker identified in our Seurat analysis of EB scRNAseq as discriminating between other cell type clusters, and the data shows the distribution of that marker in E8.25 mouse in vivo cell types. For Extended Data Fig 5c, the median is shown as a line in the box, and the outline of the box is depicted at the 25th and 75th percentile. The extended whiskers depict Q1-1.5*IQR and Q3 + 1.5*IQR. Outliers points are depicted as dots.
Extended Data Fig. 6 Related to Fig. 6.
a, FSHD1 iPSC (patient #1, 2, 3) immunostaining for pluripotency markers SOX2 and OCT3/4. Representative image from 3 independent experiments. Merge: DAPI = cyan, SOX2 = yellow, OCT4 = magenta. Scale bar = 125 micrometers. b, Thermo-Fisher Karyostat report for FSHD1 iPSC clones patients #1, 2,3. c, RT-qPCR after vehicle control or doxorubicin treatment measuring DUX4 levels in FSHD1 iPSC patient #1, non-FSHD hESC female ‘LSJ2’, and non-FSHD iPSC ‘WT33’. N = 6 biological replicates, *<0.05 FDR, One-way ANOVA. d, Western blot with N- and C-term SMCHD1 antibodies that the 2 independent clones show in Fig. 6c are KO, isogenically created in FSHD1 patient #1. CRISPR/Cas9 deletion strategy shown on right top, with the Sanger sequencing of KO clones shown on bottom right. e, Genome browser snap-shot of ATAC-seq performed in human embryos showing open chromatin signal at the 4qA LTR10C element. f, Luciferase assay testing directionality of the LTR10C element in FSHD1 patient #1 iPSC (p53 WT or isogenic p53 KO). N = 4 biological replicates. g, RNA-seq analysis from Liu, et al. Nature 2021 showing reactivation of direct p53 targets (Mdm2, Cdkn1a (p21), and Krt5) in Ythdc1 conditional knockout (cKO) mESC ± Dux KO, treated with vehicle or 4-OHT (tamoxifen) to eliminate the YTHDC1 protein. For Extended Data Fig 6c, f, the median is shown as a line in the box, and the outline of the box is depicted at the 25th and 75th percentile. The extended whiskers depict Q1-1.5*IQR and Q3 + 1.5*IQR. Outliers points are depicted as dots.
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Grow, E.J., Weaver, B.D., Smith, C.M. et al. p53 convergently activates Dux/DUX4 in embryonic stem cells and in facioscapulohumeral muscular dystrophy cell models. Nat Genet 53, 1207–1220 (2021). https://doi.org/10.1038/s41588-021-00893-0
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DOI: https://doi.org/10.1038/s41588-021-00893-0
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