Cited by 325Genetics and Neurodevelopmental DisordersEpigenetics and DNA MethylationGenomics and Chromatin Dynamics

Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells

Coffee, Bradford, Zhang, Fuping, Warren, Stephen T., Reines, Daniel·1999·Nature Genetics

Abstract

Mutation of FMR1 results in fragile X mental retardation. The most common FMR1 mutation is expansion of a CGG repeat tract at the 5' end of FMR1, which leads to cytosine methylation and transcriptional silencing. Both DNA methylation and histone deacetylation have been associated with transcriptional inactivity. The finding that the methyl cytosine-binding protein MeCP2 binds to histone deacetylases and represses transcription in vivo supports a model in which MeCP2 recruits histone deacetylases to methylated DNA, resulting in histone deacetylation, chromatin condensation and transcriptional silencing. Here we demonstrate that the 5' end of FMR1 is associated with acetylated histones H3 and H4 in cells from normal individuals, but acetylation is reduced in cells from fragile X patients. Treatment of fragile X cells with 5-aza-2'-deoxycytidine (5-aza-dC) resulted in reassociation of acetylated histones H3 and H4 with FMR1 and transcriptional reactivation, whereas treatment with trichostatin A (TSA) led to almost complete acetylated histone H4 and little acetylated histone H3 reassociation with FMR1, as well as no detectable transcription. Our results represent the first description of loss of histone acetylation at a specific locus in human disease, and advance understanding of the mechanism of FMR1 transcriptional silencing.

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Crossref · 10.1038/8807

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  • These epigenetic changes promote a heterochromatic configuration that excludes specific transcription factors and turns gene expression off.

    “These epigenetic changes promote a heterochromatic configuration that excludes the binding of specific transcription factors (19), thus turning gene expression off (20).”

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Authors
Coffee, B., Zhang, F., Warren, S. T., & Reines, D.
Affiliations
  • Emory University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Reines, Daniel
Venue
Nature Genetics
Published
1999-05
Volume
22
Issue
1
Pages
98-101
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W1558348929
Cited by
325
References
29
Citations by year
2026: 2 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 14 · 2019: 11 · 2018: 13 · 2017: 12 · 2016: 16 · 2015: 11 · 2014: 15 · 2013: 13 · 2012: 10
FWCI
13.07
Type
journal article
Language
en
Update notices
erratum (1999-06-01)
Open access
closed
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 35576, P01HD035576)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
fragile X syndrome, FMR1 gene, histone acetylation, histone H3, histone H4, transcriptional silencing, CGG repeat expansion, DNA methylation, MeCP2, histone deacetylase, decitabine, trichostatin A, transcriptional reactivation, chromatin condensation
MeSH terms
Decitabine, Acetylation, Acetyltransferases, Azacitidine, Cells, Cultured, Chromatin, DNA, Enzyme Inhibitors, Fragile X Syndrome, Histones, Humans, Hydroxamic Acids, Male, Nerve Tissue Proteins, Protein Binding, Transcription, Genetic, RNA-Binding Proteins, Saccharomyces cerevisiae Proteins, Histone Acetyltransferases, Fragile X Messenger Ribonucleoprotein 1, Fragile X Mental Retardation Protein

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