Differential regulation of the Sir2 histone.pdfVIP

Research Article Differential regulation of the Sir2 histone deacetylase gene family by inhibitors of class I and II histone deacetylases S. Kyrylenko a, O. Kyrylenko a, T. Suuronen a and A. Salminen b,* a Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, 70211 Kuopio (Finland) b Department of Neurology, University Hospital of Kuopio, P.O. Box 1777, 70211 Kuopio (Finland), e-mail: antero.salminen@uku.fi Received 28 February 2003; received after revision 19 June 2003; accepted 24 June 2003 Abstract. The Sir2 histone deacetylase gene family con- sists of seven mammalian sirtuins (SIRTs) which are NAD-dependent histone/protein deacetylases. Sir2 pro- teins regulate, for instance, genome stability by chro- matin silencing in yeast. In mammals, their function is still largely unknown. Due to the NAD+ dependency, Sir2 might be the link between metabolic activity and his- tone/protein acetylation. Regulation of gene expression also seems to play an important role in Sir2 functions, since increasing the dosage of Sir2 genes increases genome stability in yeast and Caenorhabditis elegans. We observed that the modification of histone/protein acetylation status by several class I and II histone deacetylase (HDAC) inhibitors induces differential changes in gene expression profiles of seven SIRT mR- NAs in cultured neuronal cells. SIRT2, SIRT4 and SIRT7 were upregulated, whereas SIRT1, SIRT5 and SIRT6 CMLS, Cell. Mol. Life Sci. 60 (2003) 1990–1997 1420-682X/03/091990-08 DOI 10.1007/s00018-003-3090-z ? Birkh?user Verlag, Basel, 2003 CMLS Cellular and Molecular Life Sciences were downregulated by trichostatin A (TSA) and n-bu- tyrate. The upregulation of SIRT mRNAs was inhibited by actinomycin D. Interestingly, the regulation of SIRT mRNAs was highly similar both in mouse Neuro-2a neu- roblastoma cells and post-mitotic rat primary hippocam- pal and cerebellar granule neurons. Using a chromatin immunoprecipitation technique, we showed that the up- regul