title: Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreich's ataxia can be reduced upon HDAC inhibition by vitamin B3.
abstract: Large intronic expansions of the triplet-repeat sequence (GAA.TTC) cause transcriptional repression of the Frataxin gene (FXN) leading to Friedreich's ataxia (FRDA). We previously found that GAA-triplet expansions stimulate heterochromatinization in vivo in transgenic mice. We report here using chromosome conformation capture (3C) coupled with high-throughput sequencing that the GAA-repeat expansion in FRDA cells stimulates a higher-order structure as a fragment containing the GAA-repeat expansion showed an increased interaction frequency with genomic regions along the FXN locus. This is consistent with a more compacted chromatin and coincided with an increase in both constitutive H3K9me3 and facultative H3K27me3 heterochromatic marks in FRDA. Consistent with this, DNase I accessibility in regions flanking the GAA repeats in patients was decreased compared with healthy controls. Strikingly, this effect could be antagonized with the class III histone deactylase (HDAC) inhibitor vitamin B3 (nicotinamide) which activated the silenced FXN gene in several FRDA models. Examination of the FXN locus revealed a reduction of H3K9me3 and H3K27me3, an increased accessibility to DNase I and an induction of euchromatic H3 and H4 histone acetylations upon nicotinamide treatment. In addition, transcriptomic analysis of nicotinamide treated and untreated FRDA primary lymphocytes revealed that the expression of 67% of genes known to be dysregulated in FRDA was ameliorated by the treatment. These findings show that nictotinamide can up-regulate the FXN gene and reveal a potential mechanism of action for nicotinamide in reactivating the epigenetically silenced FXN gene and therefore support the further assessment of HDAC inhibitors (HDACi's) in FRDA and diseases caused by a similar mechanism.
authors.affiliation: Gene Control Mechanisms and Disease Group, MRC Clinical Sciences Centre, Imperial College School Medicine, Hammersmith Hospital Campus. Du Cane Road, London, UK.
authors.forename: Ping K
authors.initials: PK
authors.lastname: Chan
authors.forename: Raul
authors.initials: R
authors.lastname: Torres
authors.forename: Cihangir
authors.initials: C
authors.lastname: Yandim
authors.forename: Pui P
authors.initials: PP
authors.lastname: Law
authors.forename: Sanjay
authors.initials: S
authors.lastname: Khadayate
authors.forename: Marta
authors.initials: M
authors.lastname: Mauri
authors.forename: Crina
authors.initials: C
authors.lastname: Grosan
authors.forename: Nadine
authors.initials: N
authors.lastname: Chapman-Rothe
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.forename: Mark
authors.initials: M
authors.lastname: Pook
authors.forename: Richard
authors.initials: R
authors.lastname: Festenstein
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002461:Cell Line, Transformed; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism; D004843:Epistasis, Genetic / Q000187:drug effects; D005621:Friedreich Ataxia / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D023061:Gene Order; D056426:Genetic Loci; D006570:Heterochromatin / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009536:Niacinamide / Q000494:pharmacology*; D019680:Trinucleotide Repeat Expansion; D000096923:Frataxin
chemical_list: D002843:Chromatin; D003850:Deoxyribonuclease I; D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006657:Histones; D033862:Iron-Binding Proteins; D009536:Niacinamide; D000096923:Frataxin