Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT. [Display omitted] •MeCP2 mutation severely impairs human cortical interneurons•BRD4 dysregulation contributes to abnormal transcriptome in RTT interneurons•MeCP2 mutation causes cell-type-specific impairments in human brain organoids•BET inhibition rescues RTT-like phenotypes Xiang et al. report that dysregulation of BRD4 function is a critical driver for the abnormal transcriptome in human RTT cells and that targeting BRD4 rescues molecular and functional deficiencies of human RTT cells and ameliorates RTT progression in mice.