Inhibition of BET proteins rescues neural defects in Rett syndrome [HiC-seq]

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2). Cellular heterogeneity in the brain confounds the understanding of RTT etiology. To date, how MeCP2 mutation affects defined cell types in human brain remains unclear, and effective therapeutics for RTT is lacking. Here we show that cell-type-specific transcriptome impairment and JQ1-mediated rescue in RTT cells from dorsal and ventral human forebrain organoids. We find that MeCP2 mutation severely impairs human cortical interneurons (INs). Dysregulation of MeCP2-BRD4 ChIP regulatory axis and three-dimensional genome architecture are critically involved in the abnormal transcription in RTT INs, and JQ1 strongly rescues RTT INs by resetting the aberrant chromatin binding of BRD4 ChIP. Finally, JQ1 alleviates RTT-like phenotypes in mice. These data demonstrate that BRD4 ChIP dysregulation is a critical driver for RTT etiology and targeting BRD4 ChIP is an effective therapeutic opportunity for RTT. Overall design: 3D chromation interaction profiles were generated by deep sequencing