Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, 14203, USA.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, 10065, USA.
Mol Psychiatry. 2020 Oct;25(10):2517-2533. doi: 10.1038/s41380-019-0351-2. Epub 2019 Jan 18.
Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activity-regulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.
许多在自闭症中被打乱的基因被鉴定为组蛋白修饰酶和染色质重塑酶，其中最突出的是那些介导组蛋白甲基化/去甲基化的酶。然而，组蛋白甲基转移酶在自闭症的病理生理学和治疗中的作用仍然未知。为了解决这个问题，我们使用 Shank3 基因（一种高度易患的单基因自闭症风险因素）部分缺失的小鼠模型，该基因表现出明显的自闭症样社交缺陷。我们发现，组蛋白甲基转移酶 EHMT1 和 EHMT2 以及组蛋白赖氨酸 9 二甲基化（由 EHMT1/2 特异性催化）在 Shank3 缺陷小鼠和自闭症患者死后大脑的前额叶皮层（PFC）中选择性增加。在 PFC 中用 EHMT1/2 抑制剂 UNC0642 处理或敲低 EHMT1/2，可显著挽救 Shank3 缺陷小鼠的自闭症样社交缺陷，并恢复 NMDAR 介导的突触功能。活性调节细胞骨架相关蛋白（Arc）被鉴定为 UNC0642 对 Shank3 缺陷小鼠 NMDAR 功能和社交行为的挽救作用的一个因果因素。UNC0642 治疗还恢复了 Shank3 缺陷小鼠 PFC 中涉及神经信号的一大组基因。这些结果表明，靶向组蛋白甲基转移酶以调节基因表达和改善突触缺陷可能是自闭症的一种潜在治疗策略。
