SIRT1 inhibition alleviates gene silencing in Fragile X mental retardation syndrome.
Expansion of the CGG.CCG-repeat tract in the 5' 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 to be effective, SIRT1 inhibitors may be more useful for FMR1 gene reactivation in post-mitotic cells like neurons where the effect of the gene silencing is most obvious.
Biacsi
Rea
R
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.
Kumari
Daman
D
Usdin
Karen
K
D000483:Alleles; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000201:enzymology* / Q000235:genetics*; D020868:Gene Silencing / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009281:Naphthalenes / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011753:Pyrones / Q000494:pharmacology; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors*; D019680:Trinucleotide Repeat Expansion
D001374:Azacitidine; D017931:DNA Primers; D000077209:Decitabine; D004791:Enzyme Inhibitors; D051860:Fragile X Messenger Ribonucleoprotein 1; D006657:Histones; D006877:Hydroxamic Acids; D009281:Naphthalenes; D009536:Niacinamide; D011753:Pyrones; D056564:Sirtuin 1; D037761:Sirtuins; C497683:FMR1 protein, human; C012589:trichostatin A; C444426:splitomicin; C447939:SIRT1 protein, human