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.

Rett 综合征 (RTT) 主要由甲基 CpG 结合蛋白 2 (MeCP2) 突变引起，是最常见的智力障碍之一，目前尚无有效的治疗方法。在这里，我们使用 2D 和 3D 人脑培养物来研究 MeCP2 功能。我们发现 MeCP2 突变会导致人类中间神经元 (IN) 严重异常。令人惊讶的是，BET 抑制剂 JQ1 的治疗挽救了 MeCP2 突变 IN 的分子和功能表型。我们发现 BRD4 染色质结合和增强子-启动子相互作用的异常增加是 MeCP2 突变体 IN 转录异常的基础，而 JQ1 将其恢复到正常水平。我们揭示了由 JQ1 拯救的 MeCP2 突变区域特异性人脑类器官中细胞类型特异性转录组损伤。最后，JQ1 改善了小鼠的 RTT 样表型。这些数据表明 BRD4 失调是 RTT 病因的关键驱动因素，并表明靶向 BRD4 可能是 RTT 的潜在治疗机会。