小柯机器人

美国哈佛医学院Michael E. Greenberg和Gabriella L. Boulting研究组合作取得最新进展。他们提出人类GABA能神经元活动依赖的正则规则揭示了基因调控和神经系统疾病遗传力的新模式。该研究于2021年2月4日发表于《自然-神经科学》。

因为GABA能神经回路的改变与神经系统疾病有关，所以他们对人类诱导的多能干细胞来源的GABA能神经元进行了与活动有关的转录和表观遗传学分析，类似于早期发育的纹状体。他们鉴定了在膜去极化后可诱导表达的基因，其中一些已在灵长类动物中特异性进化和/或与神经系统疾病（包括精神分裂症和自闭症谱系障碍（ASD））相关。

他们定义了人类神经元活动依赖性增强子、启动子和转录因子CREB和CRTC1的全基因组概况。他们在诱导型启动子中发现了显著的ASD遗传力富集。他们的结果表明，发育中的人类前脑GABA能神经元的活动诱导型启动子内的序列变异有助于ASD风险。

据了解，神经元活动依赖性基因表达对于大脑发育至关重要。尽管已经在小鼠中探索了神经元活性的转录和表观遗传学作用，但人类尚缺乏这种研究。

附：英文原文

Title: Activity-dependent regulome of human GABAergic neurons reveals new patterns of gene regulation and neurological disease heritability

Author: Gabriella L. Boulting, Ershela Durresi, Bulent Ataman, Maxwell A. Sherman, Kevin Mei, David A. Harmin, Ava C. Carter, Daniel R. Hochbaum, Adam J. Granger, Jesse M. Engreitz, Sinisa Hrvatin, Michael R. Blanchard, Marty G. Yang, Eric C. Griffith, Michael E. Greenberg

Issue&Volume: 2021-02-04

Abstract: Neuronal activity-dependent gene expression is essential for brain development. Although transcriptional and epigenetic effects of neuronal activity have been explored in mice, such an investigation is lacking in humans. Because alterations in GABAergic neuronal circuits are implicated in neurological disorders, we conducted a comprehensive activity-dependent transcriptional and epigenetic profiling of human induced pluripotent stem cell-derived GABAergic neurons similar to those of the early developing striatum. We identified genes whose expression is inducible after membrane depolarization, some of which have specifically evolved in primates and/or are associated with neurological diseases, including schizophrenia and autism spectrum disorder (ASD). We define the genome-wide profile of human neuronal activity-dependent enhancers, promoters and the transcription factors CREB and CRTC1. We found significant heritability enrichment for ASD in the inducible promoters. Our results suggest that sequence variation within activity-inducible promoters of developing human forebrain GABAergic neurons contributes to ASD risk. Boulting et al. profile activity-dependent gene expression and regulatory elements in human induced pluripotent stem cell-derived GABAergic neurons and uncover a possible role for calcium-responsive gene promoters of these neurons in autism risk.

DOI: 10.1038/s41593-020-00786-1

Source: https://www.nature.com/articles/s41593-020-00786-1

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
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