Nature子刊：神经干细胞发育表观遗传调控新机制

　　

　LSD1是第一个被发现的组蛋白去甲基化酶，在基因表达过程中起关键作用，但LSD1在大脑发育过程中的功能和作用机制目前还不清楚。　　

   中国科学院遗传与发育生物学研究所许执恒课题组利用胚胎颅内电转和基因敲除技术，发现LSD1参与大脑发育过程中神经干细胞（NPC）的自我更新和分化。通过CHIP-Seq实验，他们发现一个新的LSD1调控靶基因——ATN1。LSD1作用于ANT1基因3’ 端一个调控位点（命名为LBAL）。通过调控该位点的甲基化，提高ATN1的表达。

   进一步的研究表明，ATN1和LSD1具有非常类似的功能——调控神经干细胞的增殖与分化，而且表达ATN1可以挽救LSD1敲降所致表型。更重要的是该研究表明：临床药物——强心百乐明（Tranylcypromine）可以被用来预防和治疗ATN1相关的神经退行性疾病——dentatorubral-pallidoluysian atrophy (DRPLA)。　　

   该研究成果于12月18日发表在Nature Communications上（doi: 10.1038/ncomms6815）。该项目得到中科院战略性先导专项、科技部、自然科学基金委、分子发育国家重点实验室的资助。许执恒课题组的博士研究生张峰为该文章的第一作者。

大脑神经干细胞发育表观遗传调控机制

原文摘要：

Epigenetic regulation of ​Atrophin1 by ​lysine-specific demethylase 1 is required for cortical progenitor maintenance

Lysine-specific demethylase 1 (​LSD1) is involved in gene regulation and development; however, its precise function, molecular targets and underlying mechanisms during development are poorly understood. Here we show that ​LSD1 is required for neuronal progenitor cell (NPC) maintenance during cortical development. A ChIP-seq analysis identified a ​LSD1-binding site (LBAL) downstream of ​Atrophin1 (​ATN1). Surprisingly, ​tranylcypromine (​LSD1 inhibitor) treatment increased H3K4 methylation at LBAL, leading to ​ATN1 repression and NPC differentiation. Knockdown of ​LSD1 and ​ATN1 phenocopied each other in inducing NPC premature differentiation and depletion, which could be rescued by ​ATN1 overexpression, suggesting that ​LSD1 controls NPC differentiation via regulation of ​ATN1 methylation status and expression. The involvement of ​LSD1 in ​ATN1 expression and NPC maintenance were confirmed in knockout mice. These findings hint at the potential application for the clinical drug, ​tranylcypromine, in the prevention and/or treatment of ​ATN1-associated degenerative disease, dentatorubral-pallidoluysian atrophy.