sirt1 inhibition alleviates gene silencing in fragile x mental retardation syndromesirt1抑制减轻基因沉默在脆性x智力迟钝综合症.pdfVIP

SIRT1 Inhibition Alleviates Gene Silencing in Fragile X Mental Retardation Syndrome 1,2 1 1 Rea Biacsi , Daman Kumari , Karen Usdin * 1 Section on Genomic Structure and Function, Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National ¨ ¨ Institutes of Health, Bethesda, Maryland, United States of America, 2 Doctorate School of Biology, Classical and Molecular Genetics Branch, Department of Genetics, Eotvos ´ ´ Lorand University, Budapest, Hungary Abstract Expansion of the CGGNCCG-repeat tract in the 59 UTR of the FMR1 gene to .200 repeats leads to heterochromatinization of the promoter and gene silencing. This results in Fragile X syndrome (FXS), the most common heritable form of mental retardation. The mechanism of gene silencing is unknown. We report here that a Class III histone deacetylase, SIRT1, plays an important role in this silencing process and show that the inhibition of this enzyme produces significant gene reactivation. This contrasts with the much smaller effect of inhibitors like trichostatin A (TSA) that inhibit Class I, II and IV histone deacetylases. Reactivation of silenced FMR1 alleles was accompanied by an increase in histone H3 lysine 9 acetylation as well as an increase in the amount of histone H4 that is acetylated at lysine 16 (H4K16) by the histone acetyltransferase, hMOF. DNA methylation, on the other hand, is unaffected. We also demonstrate that deacetylation of H4K16 is a key downstream consequence of DNA methylation. However, since DNA methylation inhibitors require DNA replication in order