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    Establishment of histone gene regulation and cell cycle checkpoint control in human embryonic stem cells

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    Authors
    Becker, Klaus A.
    Stein, Janet L.
    Lian, Jane B.
    Van Wijnen, Andre J.
    Stein, Gary S.
    UMass Chan Affiliations
    Department of Cell Biology
    Graduate School of Biomedical Sciences
    Document Type
    Journal Article
    Publication Date
    2006-11-11
    Keywords
    Cell Cycle Proteins; Cell Nucleus; Cells, Cultured; Chromosomes; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; E2F Transcription Factors; E2F4 Transcription Factor; Embryonic Stem Cells; G1 Phase; Gene Expression Regulation, Developmental; Genes, cdc; Histones; Humans; Nuclear Proteins; RNA Stability; RNA, Messenger; Repressor Proteins
    Life Sciences
    Medicine and Health Sciences
    
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    Link to Full Text
    http://dx.doi.org/10.1002/jcp.20903
    Abstract
    Rapid self-renewal of human embryonic stem (ES) cells (NIH designation WA01 and WA09) is accommodated by an abbreviated cell cycle due to a reduction in the G1 phase. Thus, molecular mechanisms operative in ES cells may expedite the cellular commitment to progress into S phase to initiate replication of DNA and biosynthesis of histone proteins to form new chromatin. Here we show that the selective cell cycle regulated expression of individual histone H4 gene copies, which is typical for somatic cell types, is already firmly established in human ES cells. This early establishment of H4 gene regulation, which is E2F independent, is consistent with co-expression of the cognate transcriptional regulators HiNF-P and p220(NPAT). Human ES cells differ from somatic cells in the expression of members of the E2F family and RB-related pocket proteins (p105(RB1), p107(RBL1), and p130(RBL2/RB2)) that control expression of genes encoding enzymes for nucleotide metabolism and DNA synthesis. Human ES cells rapidly and robustly (>200-fold) induce the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) upon gamma-irradiation. This DNA damage response promptly reduces histone gene expression as well as mRNA levels for HiNF-P and p220(NPAT) and causes accumulation of unprocessed histone H4 precursor RNAs. Furthermore, while E2F4, E2F5 and p130(RBL2/RB2) are the major E2F and pocket protein mRNAs in actively proliferating ES cells, expression levels of E2F5, E2F6, and p105(RB1) are most strongly elevated during cell cycle arrest in cells responding to DNA damage. Our data suggest that the brief G1 phase of ES cells is supported by a potent p21(WAF1/CIP1) related DNA damage response that functions through several mechanisms to rapidly inhibit cell cycle progression. This response may alter the E2F/pocket protein combinations that control E2F dependent genes and block H4 gene expression by inhibiting histone-specific transcription factors and processing of histone gene transcripts, as well as by destabilizing histone mRNAs.
    Source
    J Cell Physiol. 2007 Feb;210(2):517-26. Link to article on publisher's site
    DOI
    10.1002/jcp.20903
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/34265
    PubMed ID
    17096384
    Related Resources
    Link to article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1002/jcp.20903
    Scopus Count
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