Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Department of Psychiatry; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mol Psychiatry. 2022 Aug;27(8):3355-3366. doi: 10.1038/s41380-022-01508-8. Epub 2022 Mar 16.
Large-scale genetic studies have revealed that the most prominent genes disrupted in autism are chromatin regulators mediating histone methylation/demethylation, suggesting the central role of epigenetic dysfunction in this disorder. Here, we show that histone lysine 4 dimethylation (H3K4me2), a histone mark linked to gene activation, is significantly decreased in the prefrontal cortex (PFC) of autistic human patients and mutant mice with the deficiency of top-ranking autism risk factor Shank3 or Cul3. A brief treatment of the autism models with highly potent and selective inhibitors of the H3K4me2 demethylase LSD1 (KDM1A) leads to the robust rescue of core symptoms of autism, including social deficits and repetitive behaviors. Concomitantly, LSD1 inhibition restores NMDA receptor function in PFC and AMPA receptor-mediated currents in striatum of Shank3-deficient mice. Genome-wide RNAseq and ChIPseq reveal that treatment of Shank3-deficient mice with the LSD1 inhibitor restores the expression and H3K4me2 occupancy of downregulated genes enriched in synaptic signaling and developmental processes. The immediate early gene tightly linked to neuronal plasticity, Egr1, is on the top list of rescued genes. The diminished transcription of Egr1 is recapitulated in PFC of autistic human patients. Overexpression of Egr1 in PFC of Shank3-deficient mice ameliorates social preference deficits. These results have for the first time revealed an important role of H3K4me2 abnormality in ASD pathophysiology, and the therapeutic potential of targeting H3K4me2 demethylase LSD1 or the downstream molecule Egr1 for ASD.
大规模的遗传研究表明，自闭症中受干扰最严重的基因是介导组蛋白甲基化/去甲基化的染色质调节剂，这表明表观遗传功能障碍在这种疾病中起着核心作用。在这里，我们发现组蛋白赖氨酸 4 二甲基化（H3K4me2），一种与基因激活相关的组蛋白标记，在自闭症患者的前额叶皮层（PFC）和具有顶级自闭症风险因素 Shank3 或 Cul3 缺陷的突变小鼠中显著减少。用高度有效和选择性的 H3K4me2 去甲基酶 LSD1（KDM1A）抑制剂短暂处理自闭症模型，可显著挽救自闭症的核心症状，包括社交缺陷和重复行为。同时，LSD1 抑制恢复了 PFC 中的 NMDA 受体功能和 Shank3 缺陷小鼠纹状体中的 AMPA 受体介导的电流。全基因组 RNAseq 和 ChIPseq 显示，用 LSD1 抑制剂处理 Shank3 缺陷小鼠可恢复富含突触信号和发育过程的下调基因的表达和 H3K4me2 占有率。与神经元可塑性紧密相关的早期基因 Egr1 是被挽救基因的首要候选基因。自闭症患者 PFC 中 Egr1 的转录减少得到了重现。在 Shank3 缺陷小鼠的 PFC 中过表达 Egr1 可改善社交偏好缺陷。这些结果首次揭示了 H3K4me2 异常在 ASD 病理生理学中的重要作用，以及靶向 H3K4me2 去甲基酶 LSD1 或下游分子 Egr1 治疗 ASD 的潜在治疗作用。
