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| Subject Categories: Chromatin & Transcription | Cell Cycle |
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| The EMBO Journal
(2002) 21, 2672–2681, doi: 10.1093/emboj/21.11.2672 |
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| Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression |
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| Gerda Lagger1, Dónal O'Carroll2, 3, Martina Rembold1, Harald Khier1, Julia Tischler1, Georg Weitzer4, Bernd Schuettengruber1, Christoph Hauser1, Reinhard Brunmeir1, Thomas Jenuwein2 and Christian Seiser1 |
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1 Institute of Medical Biochemistry, Division of Molecular Biology, University of Vienna, Vienna Biocenter, Dr Bohr-Gasse 9/2, A-1030 Vienna, Austria 2 Institute of Molecular Pathology, Vienna Biocenter, Dr Bohr-Gasse 7, A-1030 Vienna, Austria 3 Present address: Laboratory for Lymphocyte Signaling, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA 4 Institute of Medical Biochemistry, Division of Biochemistry, University of Vienna, Vienna Biocenter, Dr Bohr-Gasse 9/3, A-1030 Vienna, Austria To whom correspondence should be addressed Christian Seiser, cs@mol.univie.ac.at Received 7 December 2001; Revised 3 April 2002; Accepted 11 April 2002. |
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| Abstract |
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| Histone deacetylases (HDACs) modulate chromatin structure and transcription, but little is known about their function in mammalian development. HDAC1 was implicated previously in the repression of genes required for cell proliferation and differentiation. Here we show that targeted disruption of both HDAC1 alleles results in embryonic lethality before E10.5 due to severe proliferation defects and retardation in development. HDAC1-deficient embryonic stem cells show reduced proliferation rates, which correlate with decreased cyclin-associated kinase activities and elevated levels of the cyclin-dependent kinase inhibitors p21WAF1/CIP1 and p27KIP1. Similarly, expression of p21 and p27 is up-regulated in HDAC1-null embryos. In addition, loss of HDAC1 leads to significantly reduced overall deacetylase activity, hyperacetylation of a subset of histones H3 and H4 and concomitant changes in other histone modifications. The expression of HDAC2 and HDAC3 is induced in HDAC1-deficient cells, but cannot compensate for loss of the enzyme, suggesting a unique function for HDAC1. Our study provides the first evidence that a histone deacetylase is essential for unrestricted cell proliferation by repressing the expression of selective cell cycle inhibitors. |
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| Keywords: CDK inhibitors, chromatin, development, histone acetylation, proliferation |
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