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

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

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.

MeSH terms

  • Animals
  • Azepines / pharmacology*
  • Cells, Cultured
  • Epigenesis, Genetic
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Syndrome / drug therapy*
  • Fragile X Syndrome / metabolism*
  • Gene Expression / drug effects
  • Gene Expression Regulation / drug effects
  • Histones / metabolism
  • Mice
  • Mice, Knockout
  • Naphthyridines / pharmacology
  • Neurons / metabolism
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / metabolism*
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Triazoles / pharmacology*

Substances

  • (+)-JQ1 compound
  • 5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid
  • Azepines
  • Brd4 protein, mouse
  • Fmr1 protein, mouse
  • Histones
  • Naphthyridines
  • Nuclear Proteins
  • Transcription Factors
  • Triazoles
  • Fragile X Mental Retardation Protein