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J. Biol. Chem., Vol. 278, Issue 39, 37840-37848, September 26, 2003

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The SIN3 Deacetylase Complex Represses Genes Encoding Mitochondrial Proteins

IMPLICATIONS FOR THE REGULATION OF ENERGY METABOLISM^*,

Lori A. Pile , Paul T. Spellman  ¶, Rebeccah J. Katzenberger || and David A. Wassarman || **

From the NICHD, National Institutes of Health, Cell Biology and Metabolism Branch, Bethesda, Maryland 20892, the Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, and the ^||University of Wisconsin Medical School, Department of Pharmacology, Madison, Wisconsin 53706

Deacetylation of histones by the SIN3 complex is a major mechanism utilized in eukaryotic organisms to repress transcription. Presumably, developmental and cellular phenotypes resulting from mutations in SIN3 are a consequence of altered transcription of SIN3 target genes. Therefore, to understand the molecular mechanisms underlying SIN3 mutant phenotypes in Drosophila, we used full-genome oligonucleotide microarrays to compare gene expression levels in wild type Drosophila tissue culture cells versus SIN3-deficient cells generated by RNA interference. Of the 13,137 genes tested, 364 were induced and 35 were repressed by loss of SIN3. The 10-fold difference between the number of induced and repressed genes suggests that SIN3 plays a direct role in regulating these genes. The identified genes are distributed throughout euchromatic regions but are preferentially excluded from heterochromatic regions of Drosophila chromosomes suggesting that the SIN3 complex can only access particular chromatin structures. A number of cell cycle regulators were repressed by loss of SIN3, and functional studies indicate that repression of string, encoding the Drosophila homologue of the yeast CDC25 phosphatase, contributes to the G₂ cell cycle delay of SIN3-deficient cells. Unexpectedly, a substantial fraction of genes induced by loss of SIN3 is involved in cytosolic and mitochondrial energy-generating pathways and other genes encode components of the mitochondrial translation machinery. Increased expression of mitochondrial proteins in SIN3-deficient cells is manifested in an increase in mitochondrial mass. Thus, SIN3 may play an important role in regulating mitochondrial respiratory activity.

Received for publication, June 6, 2003 , and in revised form, July 14, 2003.

^* This work was supported in part by startup funds from the University of Wisconsin-Madison Graduate School, Medical School, and Department of Pharmacology (to D. A. W.), by the Intramural Program in the NICHD, National Institutes of Health (to L. A. P.), and by a grant from the Howard Hughes Medical Foundation to Gerald M. Rubin (to P. T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a table of genes.

^¶ An associate of the Howard Hughes Medical Institute.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of Wisconsin Medical School, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-6648; Fax: 608-262-1257; E-mail: dawassarman{at}facstaff.wisc.edu.

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