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. 3D chromation interaction profiles were generated by deep sequencing

雷特综合征（Rett syndrome, RTT）是一类由甲基CpG结合蛋白2（methyl-CpG binding protein 2, MeCP2）突变所导致的重型X连锁神经发育障碍。大脑内的细胞异质性给雷特综合征的病因学研究带来了干扰。截至目前，MeCP2突变如何影响人类大脑中的特定细胞类型，其机制仍未明确，且目前尚无针对雷特综合征的有效治疗手段。本研究显示，在源自人类背侧和腹侧前脑类器官的雷特综合征细胞中，存在细胞类型特异性的转录组损伤，且JQ1可介导对该损伤的挽救。研究发现，MeCP2突变会严重损害人类皮层中间神经元（cortical interneurons, INs）。MeCP2-BRD4 染色质免疫沉淀（ChIP）调控轴的失调与三维基因组结构异常，均与雷特综合征中间神经元的转录异常密切相关；而JQ1可通过重置BRD4 ChIP的异常染色质结合，强效挽救雷特综合征中间神经元。最终，JQ1可缓解小鼠体内的雷特综合征样表型。上述数据表明，BRD4 ChIP失调是雷特综合征病因的关键驱动因素，靶向BRD4 ChIP可为雷特综合征提供有效的治疗策略。本研究通过深度测序生成了三维染色质互作图谱。