Genome-wide profiling reveals stimulus-specific functions of p53 during differentiation and DNA damage of human embryonic stem cells.
How tumor suppressor p53 selectively responds to specific signals, especially in normal cells, is poorly understood. We performed genome-wide profiling of p53 chromatin interactions and target gene expression in human embryonic stem cells (hESCs) in response to early differentiation, induced by retinoic acid, versus DNA damage, caused by adriamycin. Most p53-binding sites are unique to each state and define stimulus-specific p53 responses in hESCs. Differentiation-activated p53 targets include many developmental transcription factors and, in pluripotent hESCs, are bound by OCT4 and NANOG at chromatin enriched in both H3K27me3 and H3K4me3. Activation of these genes occurs with recruitment of p53 and H3K27me3-specific demethylases, UTX and JMJD3, to chromatin. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in cell death and cell cycle regulation are conserved in both DNA damage and differentiation. Comparative genomic analysis of p53-targets in mouse and human ESCs supports an inter-species divergence in p53 regulatory functions during evolution. Our findings expand the registry of p53-regulated genes to define p53-regulated opposition to pluripotency during early differentiation, a process highly distinct from stress-induced p53 response in hESCs.
Program in Genes & Development, UT Graduate School in Biomedical Sciences at Houston, Center for Stem Cell & Development Biology, Department of Biochemistry & Molecular Biology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA, Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA and Dan L. Duncan Cancer Center, Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Kadir C
KC
Akdemir
Abhinav K
AK
Jain
Kendra
K
Allton
Bruce
B
Aronow
Xueping
X
Xu
Austin J
AJ
Cooney
Wei
W
Li
Michelle Craig
MC
Barton
D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D004249:DNA Damage; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D006657:Histones; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D056466:Histone Demethylases