title: Histone modifications and p53 binding poise the p21 promoter for activation in human embryonic stem cells.
abstract: The high proliferation rate of embryonic stem cells (ESCs) is thought to arise partly from very low expression of p21. However, how p21 is suppressed in ESCs has been unclear. We found that p53 binds to the p21 promoter in human ESCs (hESCs) as efficiently as in differentiated human mesenchymal stem cells, however it does not promote p21 transcription in hESCs. We observed an enrichment for both the repressive histone H3K27me3 and activating histone H3K4me3 chromatin marks at the p21 locus in hESCs, suggesting it is a suppressed, bivalent domain which overrides activation by p53. Reducing H3K27me3 methylation in hESCs rescued p21 expression, and ectopic expression of p21 in hESCs triggered their differentiation. Further, we uncovered a subset of bivalent promoters bound by p53 in hESCs that are similarly induced upon differentiation in a p53-dependent manner, whereas p53 promotes the transcription of other target genes which do not show an enrichment of H3K27me3 in ESCs. Our studies reveal a unique epigenetic strategy used by ESCs to poise undesired p53 target genes, thus balancing the maintenance of pluripotency in the undifferentiated state with a robust response to differentiation signals, while utilizing p53 activity to maintain genomic stability and homeostasis in ESCs.
authors.affiliation: Cancer &Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, 169857 Singapore.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Itahana
authors.affiliation: Stem Cell Disease Models A*STAR Institute of Medical Biology, 8A Biomedical Grove, Immunos, 138648 Singapore.|Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Genome Building, 138672 Singapore.|Translational Laboratory in Genetic Medicine, A*STAR, 8A Biomedical Grove, Immunos, 138648 Singapore.
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Computational &Systems Biology Genome Building, 138672 Singapore.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Göke
authors.affiliation: Translational Regulation in Stem Cells, A*STAR Institute of Medical Biology, 8A Biomedical Grove, Immunos, 138648 Singapore.|School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
authors.forename: Leah A
authors.initials: LA
authors.lastname: Vardy
authors.affiliation: Cancer &Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, 169857 Singapore.
authors.forename: Rachel
authors.initials: R
authors.lastname: Han
authors.affiliation: Cancer &Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, 169857 Singapore.
authors.forename: Kozue
authors.initials: K
authors.lastname: Iwamoto
authors.affiliation: Computational &Systems Biology Genome Building, 138672 Singapore.
authors.forename: Engin
authors.initials: E
authors.lastname: Cukuroglu
authors.affiliation: Stem Cell and Regenerative Biology, Genome Institute of Singapore, 60 Biopolis Street, Genome Building, 138672 Singapore.
authors.forename: Paul
authors.initials: P
authors.lastname: Robson
authors.affiliation: Translational Laboratory in Genetic Medicine, A*STAR, 8A Biomedical Grove, Immunos, 138648 Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 117597 Singapore.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.affiliation: Stem Cell Disease Models A*STAR Institute of Medical Biology, 8A Biomedical Grove, Immunos, 138648 Singapore.
authors.forename: Alan
authors.initials: A
authors.lastname: Colman
authors.affiliation: Cancer &Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, 169857 Singapore.
authors.forename: Koji
authors.initials: K
authors.lastname: Itahana
mesh_terms: D001483:Base Sequence; D002454:Cell Differentiation; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D044127:Epigenesis, Genetic; D019084:Fluorescent Antibody Technique, Indirect; D006657:Histones / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D055550:Protein Stability; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53