成年人的大脑中特定于血统的3D基因组结构和染色质互动组中的神经发育变化
Samir Rahman1,2,3,4,5, Pengfei Dong1,2,3,4,5, Pasha Apontes1,2,3,4,5,6
1Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Nucleic acids research
|October 9, 2023
概括
这是一个3D基因组.
科学领域:
- 神经科学是一个神经科学.
- 基因组学就是基因组学.
- 细胞生物学 细胞生物学
背景情况:
- 人类大脑的复杂细胞类型及其基因表达依赖于3D基因组组织,这尚未完全理解.
- 研究细胞类型特定的基因组结构对于理解神经发育和功能至关重要.
研究的目的:
- 解读细胞类型特定的基因组结构和染色质相互作用组在人类神经发育过程中的变化.
- 为了比较胎儿皮质板的3D基因组与成年神经元和脑细胞.
主要方法:
- 在人类胎儿皮质板,成年神经元和脑细胞中对3D基因组架构 (分组,TAD,循环) 的比较分析.
- 在诱导多能干细胞 (iPSC) 衍生神经元中进行基因操纵的CRISPR干扰 (CRISPRi).
- 全基因组协会研究 (GWAS) 位置分析.
主要成果:
- 与神经元相比,神经元表现出较弱的基因组细分,但较强的拓关联域 (TADs),而这些TADs是在胎儿发育期间出现的.
- 神经元基因组显示出更强烈的向压制性部分的转变,差异性TAD边界与神经发育基因促进者有关.
- 在神经元中通过CRISPRi破坏CNTNAP2,导致在差异边界的绝缘损失,影响基因转录.
- 神经发育期间的染色体循环重新连接与转录和功能变化相关.
- 胎儿皮层中的差异循环与自闭症GWAS位点有关,涉及神经精神疾病中的染色体相互作用.
- 神经发育涉及增强剂-促进剂循环的形成,这些循环可对控制突触活动的基因进行上调.
结论:
- 在人类神经发育过程中,3D基因组经历了显著的细胞类型特异性改变.
- 3D基因组结构的变化,包括TAD和染色质环,与基因调节,神经发育过程和突触活动有关.
- 3D基因组和染色体相互作用的失调可能导致神经精神疾病,如自闭症.
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