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

• Published in: Cell Vol. 170; no. 6; pp. 1209 - 1223.e20
• Main Authors: Korb, Erica, Herre, Margaret, Zucker-Scharff, Ilana, Gresack, Jodi, Allis, C. David, Darnell, Robert B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.09.2017
• Subjects: Animals; Azepines - pharmacology; Brd4; Cells, Cultured; chromatin; Epigenesis, Genetic; FMRP; Fragile X Mental Retardation Protein - metabolism; Fragile X Syndrome - drug therapy; Fragile X Syndrome - metabolism; FXS; Gene Expression - drug effects; Gene Expression Regulation - drug effects; histones; Histones - metabolism; Mice; Mice, Knockout; Naphthyridines - pharmacology; Neurons - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Phenazines; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Transcription, Genetic; Triazoles - pharmacology; FXS; histones; chromatin; FMRP; Brd4
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.07.033

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. [Display omitted] •FMRP regulates chromatin-associated proteins in addition to synaptic proteins•Misregulation of chromatin contributes to Fragile X syndrome•Inhibition of Brd4 can alleviate transcriptional dysfunction and phenotypes of FXS Loss of FMRP results in widespread epigenetic misregulation, and targeting transcription can correct deficits in a mouse model of Fragile X syndrome.