The SIN3 Deacetylase Complex Represses Genes Encoding Mitochondrial Proteins

Abstract

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 ϳ10-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 G 2 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.

mSin3A corepressor regulates diverse transcriptional networks governing normal and neoplastic growth and survival

“…Consistent with findings in Drosophila, mSin3A deletion resulted in the up-regulation of genes involved in cytosolic and mitochondrial energy-generating pathways (Pdk1,Mrsp23,Oghd,Adac9,Bdh,Got2,Hadh2,Cs,Fxc1,Prdx3), strengthening the provocative role for mSin3A in the regulation of mitochondrial respiratory activity (Pile et al 2003; see below). Finally, mSin3A regulates the expression of several genes involved in DNA replication (Rpa1,Lig1,Mcm4,Mcm5,Mcm7,Nap1l1) providing a basis for the observed defects in DNA replication upon deletion of mSin3A, and strengthening the case for a direct role for mSin3A in the DNA replication process.…”

Metabolic Reprogramming in Dietary Restriction

“…In the absence of this hormone, the ecdysone receptor complex interacts with transcriptional repressors Rpd3 and Sin3 [41]. What is interesting about this, from our point of view, is that reduction of Rpd3 extends life span in flies [42] and reduction in Sin3 causes upregulation of genes involved in the oxidative metabolism of fatty acid to acetyl-CoA and genes involved in mitochondrial oxidative phosphorylation [43]. The similarity between the ecdysone receptor complex and the nuclear hormone complexes in mammalian systems has led to speculation that the mammalian counterparts may also participate in the regulation of aging [44].…”

Dissecting the Biological Functions of Drosophila Histone Deacetylases by RNA Interference and Transcriptional Profiling

“…The decrease of string, which encodes the Drosophila homolog of the CDC25 phosphatase, may be particularly relevant as its elimination was shown to be sufficient to cause G 2 arrest in S2 cells. In addition, downregulation of string and G 2 arrest was also observed by others upon RNAi of the HDAC1-recruiting SIN3 co-repressor (39,40) (also see below).…”

“…This similarity is not unexpected because DHDAC1 is thought to be involved in the transcriptional repressor functions of SIN3. We therefore compared the published microarray profile of SIN3 RNAi (40) with our TSA or DHDAC1 RNAi data. Significant overlaps were detected between the published SIN3 and our DHDAC1 and TSA signatures (Fig.…”