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Cell. 2017 Sep 7;170(6):1209-1223.e20. doi: 10.1016/j.cell.2017.07.033. Epub 2017 Aug 17.

Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition.

Author information

1
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
2
Laboratory of Molecular Neuro-oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
3
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10065, USA.
4
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. Electronic address: alliscd@rockefeller.edu.
5
Laboratory of Molecular Neuro-oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA. Electronic address: darnelr@rockefeller.edu.

Abstract

Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism. FXS results from the loss of function of fragile X mental retardation protein (FMRP), which represses translation of target transcripts. Most of the well-characterized target transcripts of FMRP are synaptic proteins, yet targeting these proteins has not provided effective treatments. We examined a group of FMRP targets that encode transcriptional regulators, particularly chromatin-associated proteins. Loss of FMRP in mice results in widespread changes in chromatin regulation and aberrant gene expression. To determine if targeting epigenetic factors could reverse phenotypes associated with the disorder, we focused on Brd4, a BET protein and chromatin reader targeted by FMRP. Inhibition of Brd4 function alleviated many of the phenotypes associated with FXS. We conclude that loss of FMRP results in significant epigenetic misregulation and that targeting transcription via epigenetic regulators like Brd4 may provide new treatments for FXS.

KEYWORDS:

Brd4; FMRP; FXS; chromatin; histones

PMID:
28823556
PMCID:
PMC5740873
DOI:
10.1016/j.cell.2017.07.033
[Indexed for MEDLINE]
Free PMC Article

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