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

An Erratum to this article was published on 01 June 1999

Abstract

Mutation of FMR1 results in fragile X mental retardation1. The most common FMR1 mutation is expansion of a CGG repeat tract at the 5´ end of FMR1 (refs 2, 3, 4), which leads to cytosine methylation and transcriptional silencing5,6. Both DNA methylation and histone deacetylation have been associated with transcriptional inactivity7,8,9. The finding that the methyl cytosine-binding protein MeCP2 binds to histone deacetylases and represses transcription in vivo10,11 supports a model in which MeCP2 recruits histone deacetylases to methylated DNA, resulting in histone deacetylation, chromatin condensation and transcriptional silencing12. 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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Figure 1: Chromatin immunoprecipitation and transcription of FMR1.
Figure 2: Chromatin immunoprecipitation and transcription of FMR1 after 5-aza-dC treatment.
Figure 3: Chromatin immunoprecipitation and transcription of FMR1 after TSA treatment.

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Acknowledgements

We thank C.D. Allis for anti-phospho-H3 antisera and helpful discussions and T. Bestor, G. MacGregor, J. Boss, J. Lucchesi, P. Vertino and X. Cheng for helpful discussions. S.T.W. is an investigator of the Howard Hughes Medical Institute. This work was supported in part by NIH grant HD35576.

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Correspondence to Daniel Reines.

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Coffee, B., Zhang, F., Warren, S. et al. Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. Nat Genet 22, 98–101 (1999). https://doi.org/10.1038/8807

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