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Molecular and Cellular Biology, April 2004, p. 3132-3139, Vol. 24, No. 8
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.8.3132-3139.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of Mammalian Epithelial Differentiation and Intestine Development by Class I Histone Deacetylases

Liqiang Tou,1,2 Qiang Liu,1,2 and Ramesh A. Shivdasani1,2,3*

Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute,1 Department of Medicine, Harvard Medical School,2 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts3

Received 14 November 2003/ Returned for modification 9 January 2004/ Accepted 16 January 2004

The biochemical mechanisms underlying epigenetic control of gene expression are increasingly well known. In contrast, the contributions of individual modifications toward activation of lineage-specific genes during vertebrate development are poorly understood. Class II histone deacetylases (HDACs), which show restricted tissue distribution, regulate muscle-specific gene expression, in part through interactions with myogenic transcription factors. We have combined gene expression profiling with manipulation of fetal mouse intestinal tissue to define roles for other regulatory factors. We found that in the developing mouse intestine class I HDACs are confined to the prospective epithelium and that their levels decline coincidently with activation of differentiation genes, suggesting a functional relationship between these events. Overexpression of wild-type but not of mutant HDACs 1 and 2 in fetal intestine explants reverses expression of certain maturation markers. HDAC inhibitors, including the selective class I antagonist valproic acid, activate the same genes prematurely and accelerate cytodifferentiation. Chromatin immunoprecipitation of freshly isolated organs reveals early HDAC2 occupancy at differentiation gene promoters and corresponding histone hypoacetylation that reverses as HDAC levels fall. Thus, modulation of endogenous class I HDAC levels represents a previously unappreciated mechanism to enable onset of tissue-restricted gene expression in a developing mammalian organ.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, One Jimmy Fund Way, Boston, MA 02115. Phone: (617) 632-5746. Fax: (617) 632-4471. E-mail: ramesh_shivdasani{at}dfci.harvard.edu.

Molecular and Cellular Biology, April 2004, p. 3132-3139, Vol. 24, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.8.3132-3139.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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