近日，
在这项研究中，该课题组用snMultiomics分析了26个供体的人类妊娠中期新皮层。研究组观察到神经祖细胞和皮质丘脑神经元减少，脑外神经元增加，并伴有加速的神经元特化。研究团队发现了基因表达、染色质可及性和影响神经发生、规范和成熟的细胞相互作用网络的广泛变化；以及指导这些过程的基因调控网络，包括人类21号染色体（HSA21）编码基因的下游。课题组研究人员发现了与其他神经发育障碍共享的细胞特异性分子通路，并在DS改变的染色质中富集了全基因组关联研究信号。总之，他们的数据揭示了一系列分子失调，概述了退行性椎体滑移的早期步骤，为未来的治疗靶点提供了基础。
据悉，唐氏综合症（DS）是智力残疾最常见的遗传主题，但驱动这种发育障碍的细胞和分子机制尚不清楚。
附：英文原文
Title: A single-cell multiomic analysis identifies molecular and gene-regulatory mechanisms dysregulated in developing Down syndrome neocortex
Author: Celine K. Vuong, Alexis Weber, Patrick Seong, Nana Matoba, Yu-Jen Chen, Jordan Peyer, Shahab Younesi, Angelo Salinda, Daniel Gomez, Gabriella Rivas, Abril Morales, Beck Shafie, Pan Zhang, Susanne Nichterwitz, Le Qi, Nolan T. Fernandez, Emily Friedman, Michael I. Love, Michael J. Gandal, Daniel H. Geschwind, William E. Lowry, Jason L. Stein, Luis de la Torre-Ubieta
Issue&Volume: 2026-04-23
Abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability, yet the cellular and molecular mechanisms driving this developmental disorder remain unclear. In this study, we profiled human mid-gestation neocortex with snMultiomics across 26 donors. We observed a reduction in neural progenitors and corticothalamic neurons and an increase of intratelencephalic neurons, accompanied by accelerated neuronal specification. We uncovered widespread changes in gene expression, chromatin accessibility, and cell interaction networks affecting neurogenesis, specification, and maturation; and in gene-regulatory networks directing these processes, including those downstream of human chromosome 21 (HSA21)–encoded genes. We identified cell-specific molecular pathways shared with other neurodevelopmental disorders and enrichment of genome-wide association study signals in DS-altered chromatin. Together, our data revealed a cascade of molecular dysregulation outlining the earliest steps in DS, providing a foundation for future therapeutic targets.
DOI: aea1259
Source: https://www.science.org/doi/10.1126/science.aea1259