美国加州大学Daniel A. Lim研究团队的最新研究揭示了哺乳动物大脑发育过程中与核区室相关的不同基因组结构。相关论文于2021年7月8日发表在国际学术期刊《自然-神经科学》杂志上。

在本研究中，研究人员利用CUT和RUN技术 (GO-CaRT) 从发育小鼠、猕猴和人类大脑的不同区域生成了基因组组织，以描绘两个核隔室（核层和核斑点）的相互作用。体内细胞中的核纤层关联域 (LAD) 结构与培养细胞的结构不同，包括之前认为不随细胞类型改变的LAD主要差异。在小鼠和人前脑中，背侧和腹侧神经前体细胞在LAD结构上存在差异，这与其区域特征相对应。人和小鼠皮层中的LAD包含转录高度活跃的子域，其特征是组蛋白H3 9位赖氨酸二甲基化的广泛缺失。

人、猕猴和小鼠大脑中进化保守的LAD富含与突触功能相关的转录活性神经基因。通过将GO-CaRT 图与全基因组关联研究数据相结合，研究发现斑点相关结构域富含精神分裂症风险基因座，表明这些疾病相关遗传变异与特定核结构之间存在物理关系。该工作为理解大脑发育和疾病中不同核区室与基因组功能之间的关系提供了新思路。

据介绍，核区室被认为在基因组三维组织和基因表达中发挥功能。尚不清楚哺乳动物大脑中核区室相关基因组组织的结构和动力学。

附：英文原文

Title: Distinct nuclear compartment-associated genome architecture in the developing mammalian brain

Author: Sajad Hamid Ahanger, Ryan N. Delgado, Eugene Gil, Mitchel A. Cole, Jingjing Zhao, Sung Jun Hong, Arnold R. Kriegstein, Tomasz J. Nowakowski, Alex A. Pollen, Daniel A. Lim

Issue&Volume: 2021-07-08

Abstract: Nuclear compartments are thought to play a role in three-dimensional genome organization and gene expression. In mammalian brain, the architecture and dynamics of nuclear compartment-associated genome organization is not known. In this study, we developed Genome Organization using CUT and RUN Technology (GO-CaRT) to map genomic interactions with two nuclear compartments—the nuclear lamina and nuclear speckles—from different regions of the developing mouse, macaque and human brain. Lamina-associated domain (LAD) architecture in cells in vivo is distinct from that of cultured cells, including major differences in LADs previously considered to be cell type invariant. In the mouse and human forebrain, dorsal and ventral neural precursor cells have differences in LAD architecture that correspond to their regional identity. LADs in the human and mouse cortex contain transcriptionally highly active sub-domains characterized by broad depletion of histone-3-lysine-9 dimethylation. Evolutionarily conserved LADs in human, macaque and mouse brain are enriched for transcriptionally active neural genes associated with synapse function. By integrating GO-CaRT maps with genome-wide association study data, we found speckle-associated domains to be enriched for schizophrenia risk loci, indicating a physical relationship between these disease-associated genetic variants and a specific nuclear structure. Our work provides a framework for understanding the relationship between distinct nuclear compartments and genome function in brain development and disease.

DOI: 10.1038/s41593-021-00879-5

Source: https://www.nature.com/articles/s41593-021-00879-5