title: Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.
abstract: Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS) gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11) suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT) inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America. petertod@umich.edu
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
authors.forename: Seok Yoon
authors.initials: SY
authors.lastname: Oh
authors.forename: Amy
authors.initials: A
authors.lastname: Krans
authors.forename: Udai B
authors.initials: UB
authors.lastname: Pandey
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Di Prospero
authors.forename: Kyung-Tai
authors.initials: KT
authors.lastname: Min
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D000107:Acetylation; D000328:Adult; D000369:Aged, 80 and over; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005123:Eye / Q000201:enzymology / Q000294:innervation / Q000473:pathology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D020868:Gene Silencing; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D018911:Trinucleotide Repeats; D000099186:Histone Deacetylase 3
chemical_list: D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D051860:Fragile X Messenger Ribonucleoprotein 1; D051548:Histone Acetyltransferases; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D006657:Histones; D000099186:Histone Deacetylase 3; C556904:HDAC11 protein, Drosophila; C425683:HDAC6 protein, Drosophila