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PMID: 16921367 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia.

Nature chemical biology ·Vol. 2 ·No. 10 ·2006-10-00 ·Pages 551-8

Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld JM

Abstract

Expansion of GAA x TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the molecular basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these molecules directly affect the histones associated with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia.

MeSH Terms

Acetylation Alleles Anilides/chemical synthesis,chemistry,pharmacology Cell Line Cells, Cultured Dose-Response Relationship, Drug Enzyme Inhibitors/chemistry,pharmacology,therapeutic use Friedreich Ataxia/drug therapy,genetics Gene Expression Regulation/drug effects Gene Silencing/drug effects HeLa Cells Heterochromatin/drug effects,genetics Histone Deacetylase Inhibitors Histones/chemistry,drug effects,metabolism Humans Iron-Binding Proteins/biosynthesis,drug effects Molecular Structure RNA, Messenger/drug effects,genetics Transcription, Genetic/drug effects

Chemicals

Anilides Enzyme Inhibitors Heterochromatin Histone Deacetylase Inhibitors Histones Iron-Binding Proteins N1-(2-aminophenyl)-N8-phenyloctanediamide RNA, Messenger frataxin

Authors & Affiliations

6 authors, click to expand affiliations / ORCID

Herman David

Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.

Jenssen Kai

Burnett Ryan

Soragni Elisabetta

Perlman Susan L

Gottesfeld Joel M

Article Info

Journal

Nature chemical biology

Abbr.

Nat Chem Biol

ISSN

1552-4450

DOI

10.1038/nchembio815

Published

2006-10-00

Epub

2006-00-20

Pages

551-8

Language

English

Region

United States

NLM ID

101231976

Subset

Grants

NINDS NIH HHS · R21 NS048989 · United States

Databases

PubChem-Substance

14710626, 14710627, 14710628, 14710629, 14710630, 14710631, 14710632, 14710633, 14710634, 14710635, 14710636, 14710637, 14710638, 14710639, 14710640, 14710641, 14710642, 14710643, 14710644, 14710645, 14710646, 14710647, 14710648, 14710649, 14710650, 14710651, 14710652, 14710653, 14710654, 14710655, 14710656, 14710657, 14710658, 14710659, 14710660

Corrections

ErratumIn

CommentIn

PMID: 16983383

External Links

PubMed source DOI: 10.1038/nchembio815 View journal details

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Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia.

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