单细胞基因组学揭示的 ASD 中的分子级联和细胞类型特异性特征。

Molecular cascades and cell type-specific signatures in ASD revealed by single-cell genomics.

机构信息

Program in Neurobehavioral Genetics and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

出版信息

Science. 2024 May 24;384(6698):eadh2602. doi: 10.1126/science.adh2602.

DOI:10.1126/science.adh2602

PMID:38781372

Abstract

Genomic profiling in postmortem brain from autistic individuals has consistently revealed convergent molecular changes. What drives these changes and how they relate to genetic susceptibility in this complex condition are not well understood. We performed deep single-nucleus RNA sequencing (snRNA-seq) to examine cell composition and transcriptomics, identifying dysregulation of cell type-specific gene regulatory networks (GRNs) in autism spectrum disorder (ASD), which we corroborated using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) and spatial transcriptomics. Transcriptomic changes were primarily cell type specific, involving multiple cell types, most prominently interhemispheric and callosal-projecting neurons, interneurons within superficial laminae, and distinct glial reactive states involving oligodendrocytes, microglia, and astrocytes. Autism-associated GRN drivers and their targets were enriched in rare and common genetic risk variants, connecting autism genetic susceptibility and cellular and circuit alterations in the human brain.

摘要

对自闭症个体死后大脑进行的基因组分析一直揭示出趋同的分子变化。这些变化是由什么驱动的，以及它们与这种复杂疾病的遗传易感性有何关系，目前还不是很清楚。我们进行了深度单细胞 RNA 测序（snRNA-seq），以检查细胞组成和转录组学，确定了自闭症谱系障碍（ASD）中特定细胞类型基因调控网络（GRN）的失调，我们使用单细胞转座酶可及染色质测序（snATAC-seq）和空间转录组学进行了验证。转录组变化主要是细胞类型特异性的，涉及多种细胞类型，最突出的是半球间和胼胝体投射神经元、浅层内的中间神经元，以及涉及少突胶质细胞、小胶质细胞和星形胶质细胞的不同胶质反应状态。与自闭症相关的 GRN 驱动因子及其靶基因在罕见和常见的遗传风险变异中富集，将自闭症遗传易感性与人类大脑中的细胞和回路改变联系起来。