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在人体多能干细胞中,LINE-1逆转录子调节 cis 作用的转录控制,并调节早期的大脑发育

Anita Adami¹, Raquel Garza¹, Patricia Gerdes¹

¹Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden.

|August 23, 2025

概括

长间隔的核元素 (L1s) 在人类发育中是活跃的,影响神经分化. 沉默L1s改变了大脑器官的发育,揭示了它们在人类特异性中枢神经系统 (CNS) 过程中的作用.

科学领域:

遗传学
发育生物学
神经科学

背景情况:

长间隔的核元素 (L1s) 是移动的遗传元素,有助于基因组的进化.
在人类发育,特别是中枢神经系统 (CNS) 中L1逆转移体的作用的理解是有限的.
在机械研究中对人类L1表达的描述和操纵存在挑战.

研究的目的:

在人类发育背景下研究L1逆转移体的表达和功能影响.
探索L1衍生转录在神经分化和大脑发育中的机制性作用.
评估L1s对人类特异性中枢神经系统的贡献.

主要方法:

在人类诱导多能干细胞和脑器官中分析L1表达.
与表观遗传状态的L1促进体活性相关.
针对L1的CRISPR干扰 (CRISPRi).
鉴定L1衍生化学转录.
在L1沉默后评估神经分化和器官尺寸.

主要成果:

数以千计的人类特异性L1整合物在人类干细胞和大脑器官中表达.
L1促进剂活性有所变化,与活性表观遗传标记相关.
通过CRISPRi介导的L1沉默识别了近百个由L1衍生的合并的仿真转录.
导致神经区分程序发生变化.
在L1沉默后观察到大脑器官体积的减少.

结论:

在人类发育过程中表达和表观遗传调节L1逆转录和它们的衍生转录.
L1s在神经分化和人类中枢神经系统发育中发挥着功能性作用.
对L1的有针对性操纵提供了他们对发展计划的贡献的见解.

关键词:

一号线大脑类器官表观遗传学一个进化其他类型神经发育非编码基因组多能性可转移的元素

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