组蛋白甲基化在基因表达调控和细胞功能调控中起到关键的作用。近年来，组蛋白甲基转移酶的基因突变被报道和一些发育性的疾病有密切的关系。我们组首次发现Ash1l这种组蛋白甲基转移酶在神经系统中的功能。临床研究发现其是抽动秽语症和孤独症等神经发育疾病的易感基因之一。据此，我们发现Ash1l+/-小鼠出现了一种以不自主运动运动抽动和发声抽动等表型。由于该病的病因以及发病机制尚不明确，没有有效的治疗手段，缺乏特异性的治疗药物。因此本研究计划利用Ash1l+/-小鼠，与神经元活动报道小鼠，对激活的神经元进行高通量转录组测序以及染色质免疫共沉淀测序，筛选出Ash1l下游分子中直接导致相关神经发育疾病的候选基因。接下来利用分子和细胞学手段结合行为学手段对Ash1l的功能与下游致病基因的调控机制和生理功能进行研究，进而确定Ash1l突变导致疾病的分子机制以及其表观遗传学调控手段。

Post-translational methylation of lysine residues on histone tails is a key dynamic chromatin modification and underpins gene regulation and several cellular processes. Many lines of evidence support that variants causing haploinsufficiency of histone lysine methyltransferases are frequently encountered in individuals with developmental disorders. .Ash1L is a histone methyltransferases and also one of risk genes of Tourette syndrome (TS), which is a childhood onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders, and the molecular and epigenetic mechanism for TS remain largely unknown. In our previous study, Ash1l+/- mice showed tic behavior, which can be rescued by tic-relieving drug haloperidol. Therefore, comparing RNA-seq and CHIP-seq data in Ash1l+/- mice and WT mice, we were able to screen down-stream candidate genes involve in Ash1l haploinsufficiency induced pathology. Further analysis of these candidate genes, in Ash1l+/- mice with series of biotechnologies, will help to understand the molecular and epigenetic mechanism underlying TS and identify potential novel drug targets, which would be specific to relief the TS symptoms with less side effects.