Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression.
Journal: 2002/July - EMBO Journal
ISSN: 0261-4189
Abstract:
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 p21(WAF1/CIP1) and p27(KIP1). 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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EMBO J 21(11): 2672-2681

Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression

+2 authors
Institute of Medical Biochemistry, Division of Molecular Biology, University of Vienna, Vienna Biocenter, Dr Bohr-Gasse 9/2, Institute of Molecular Pathology, Vienna Biocenter, Dr Bohr-Gasse 7 and Institute of Medical Biochemistry, Division of Biochemistry, University of Vienna, Vienna Biocenter, Dr Bohr-Gasse 9/3, A-1030 Vienna, Austria Present address: Laboratory for Lymphocyte Signaling, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA Corresponding author e-mail: cs@mol.univie.ac.at
Received 2001 Dec 7; Revised 2002 Apr 3; Accepted 2002 Apr 11.

Abstract

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 p21 and p27. 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.

Keywords: CDK inhibitors/chromatin/development/histone acetylation/proliferation
Abstract

The genotype was determined by Southern blot analysis or PCR. ND, not determined.

Acknowledgements

We thank G.Brosch, E.Seto, D.Linzer, B.Hermann, M.Lachner, M.Baccarini and C.Sardet for reagents, A.Neubueser and F.Probst for technical advice, A.Matejowics, E.Simboeck and the Vienna Biocenter Animal Facility for valuable help, A.Neubueser, M.Posch, F.Probst, V.Kurtev, J.-P.David and M.Schreiber for critical reading of this manuscript, and E.Wintersberger for initiating this project. C.S. was supported by the Austrian FWF ({"type":"entrez-protein","attrs":{"text":"P13068","term_id":"125973","term_text":"P13068"}}P13068-GEN and {"type":"entrez-protein","attrs":{"text":"P14909","term_id":"112990","term_text":"P14909"}}P14909-GEN).

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