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

Abstract

SUMMARY 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.

FMRP Control of Ribosome Translocation Promotes Chromatin Modifications and Alternative Splicing of Neuronal Genes Linked to Autism

“…In most cases, however, mutations in epigenetic modifiers result in 6 up or down regulation of transcription. Indeed, previously identified epigenetic changes in FXS 7 model mice by Korb et al (2017), particularly H3K4me3, H4K8ac, and H4K16ac, were responsible 8 for widespread changes in transcription in cortical neurons and the cerebellum. Importantly, these 9 investigators could rescue several FXS pathophysiologies, many of which resemble those in 10 autism, by targeting the epigenetic reader protein Brd4.…”

Identification of FMRP target genes expressed in corticogenesis: implication for common phenotypes among neurodevelopmental disorders

“…Functions of FMRP have been reported to include regulation of translation, transport, and stability (De Rubeis and Bagni, 2010;Darnell et al, 2011;Ascano et al, 2012;La Fata et al, 2014;Pilaz et al, 2016;Liu et al, 2018). Although mechanisms are not fully elucidated at molecular and cellular levels, several FMRP mRNA targets are linked to various neurobiological processes such as neuronal migration and circuitry formation (La Fata et al, 2014), synaptogenesis (Darnell et al, 2011), DNA damage response (Alpatov et al, 2014), and epigenetic regulation (Korb et al, 2017). Therefore, to identify mRNAs that are controlled by FMRP is essential for elucidation of its roles in brain development by controlling the target molecules and for determination of its contribution to pathogenesis of FXS and related neurodevelopmental disorders.…”

“…In our study, we analyzed expression of ASD-related FMRP mRNA targets in the cortical primordium of Fmr1-KO by RT-qPCR. Only few studies have previously examined FMRP regulation on its targets at the mRNA level (Brown et al, 2001;Korb et al, 2017;Liu et al, 2018). These reports do not directly demonstrate the mechanistic role of FMRP on the transcription of its target genes, but they provide clues that mRNA levels are altered if FMRP function is impaired.…”

“…This results in the hypermethylation and transcriptional silencing of the gene, which lead to the loss of its product fragile X mental retardation 1 protein (FMRP) (Verkerk et al, 1991;Ashley Jr. et al, 1993;Bakker et al, 1994;Crawford et al, 2001;Garber et al, 2008). FMRP is a polyribosome-associated RNA-binding protein (RBP) that selectively targets specific mRNAs, regulates its translation, transport, and stability, as well as histone modification and chromatin remodeling (Bassell and Warren, 2008;De Rubeis and Bagni, 2010;Alpatov et al, 2014;Korb et al, 2017). Hence, FMRP is a multifunctional protein that could be involved in diverse processes, not limited to the mRNA lifecycle.…”

The K-Cl co-transporter 2 is a point of convergence for multiple autism spectrum disorder and epilepsy risk gene products

“…KCC2 is associated with multiple ASD/Epi risk genes, that are targets for FMR1 As altered KCC2 function has been implicated in ASD and epilepsy, we compiled a list of ASDand epilepsy-associated genes from SFARI (FMRP targets) (36), and EpilepsyGene (37) ( Table S5). We compared this list with the top 150 KCC2-associated proteins in both the 600 and 800 kDa bands.…”