研究人员进行了深度单核RNA测序（snRNA-seq）以检查细胞组成和转录组学，发现了ASD中细胞类型特异性基因调控网络（GRN）的失调，研究人员使用单核转座酶可及性染色质测序（snATAC-seq）和空间转录组学证实了这一点。
转录组学变化主要具有细胞类型特异性，涉及多种细胞类型，其中最突出的是半球间和胼胝体投射神经元、表层内的中间神经元，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。自闭症相关的GRN驱动因子及其靶标富集于罕见和常见的遗传风险变异中，从而将自闭症遗传易感性与人脑中的细胞和回路改变联系起来。
据了解，对自闭症患者死后大脑进行的基因组剖析不断揭示出趋同的分子变化。这些变化的驱动因素是什么，以及它们与这种复杂疾病的遗传易感性之间的关系如何，目前还不十分清楚。
附：英文原文
Title: Molecular cascades and cell type–specific signatures in ASD revealed by single-cell genomics
Author: Brie Wamsley, Lucy Bicks, Yuyan Cheng, Riki Kawaguchi, Diana Quintero, Michael Margolis, Jennifer Grundman, Jianyin Liu, Shaohua Xiao, Natalie Hawken, Samantha Mazariegos, Daniel H. Geschwind
Issue&Volume: 2024-05-24
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.
DOI: adh2602
Source: https://www.science.org/doi/10.1126/science.adh2602