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Molecular and Cellular Biology, November 2006, p. 7913-7928, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.01220-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Negative and Positive Regulation of Gene Expression by Mouse Histone Deacetylase 1{triangledown}

Gordin Zupkovitz,1 Julia Tischler,1,{dagger} Markus Posch,2,{ddagger} Iwona Sadzak,1,§ Katrin Ramsauer,3 Gerda Egger,1,¶ Reinhard Grausenburger,1 Norbert Schweifer,2 Susanna Chiocca,4 Thomas Decker,3 and Christian Seiser1*

Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna Biocenter, A-1030 Vienna, Austria,1 Boehringer Ingelheim Austria, A-1121 Vienna, Austria,2 Max F. Perutz Laboratories, Institute of Microbiology and Genetics, University of Vienna, Vienna Biocenter, A-1030 Vienna, Austria,3 European Institute of Oncology, Department of Experimental Oncology, 20141 Milan, Italy4

Received 6 July 2006/ Returned for modification 17 July 2006/ Accepted 21 August 2006

Histone deacetylases (HDACs) catalyze the removal of acetyl groups from core histones. Because of their capacity to induce local condensation of chromatin, HDACs are generally considered repressors of transcription. In this report, we analyzed the role of the class I histone deacetylase HDAC1 as a transcriptional regulator by comparing the expression profiles of wild-type and HDAC1-deficient embryonic stem cells. A specific subset of mouse genes (7%) was deregulated in the absence of HDAC1. We identified several putative tumor suppressors (JunB, Prss11, and Plagl1) and imprinted genes (Igf2, H19, and p57) as novel HDAC1 targets. The majority of HDAC1 target genes showed reduced expression accompanied by recruitment of HDAC1 and local reduction in histone acetylation at regulatory regions. At some target genes, the related deacetylase HDAC2 partially masks the loss of HDAC1. A second group of genes was found to be downregulated in HDAC1-deficient cells, predominantly by additional recruitment of HDAC2 in the absence of HDAC1. Finally, a small set of genes (Gja1, Irf1, and Gbp2) was found to require HDAC activity and recruitment of HDAC1 for their transcriptional activation. Our study reveals a regulatory cross talk between HDAC1 and HDAC2 and a novel function for HDAC1 as a transcriptional coactivator.

* Corresponding author. Mailing address: Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna Biocenter, Dr. Bohr-Gasse 9/2, A-1030 Vienna, Austria. Phone: 431 4277 61770. Fax: 431 4277 9617. E-mail: christian.seiser{at}meduniwien.ac.at.

{triangledown} Published ahead of print on 28 August 2006.

{dagger} Present address: The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom.

{ddagger} Present address: Wellcome Trust Biocentre, University of Dundee, Dundee DD1 5EH, United Kingdom.

§ Present address: Max F. Perutz Laboratories, Institute of Microbiology and Genetics, University of Vienna, Vienna Biocenter, A-1030 Vienna, Austria.

Present address: Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-9181.

Molecular and Cellular Biology, November 2006, p. 7913-7928, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.01220-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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