A single-cell multiomic analysis identifies molecular and gene-regulatory mechanisms dysregulated in developing Down syndrome neocortex

• 成果类型: Article
• 署名作者: Vuong, Celine K.; Weber, Alexis; Seong, Patrick; Matoba, Nana; Chen, Yu-Jen; Peyer, Jordan; Younesi, Shahab; Salinda, Angelo; Gomez, Daniel; Rivas, Gabriella; Morales, Abril; Shafie, Beck; Zhang, Pan; Nichterwitz, Susanne; Qi, Le; Fernandez, Nolan T.; Friedman, Emily; Love, Michael I.; Gandal, Michael J.; Geschwind, Daniel H.; Lowry, William E.; Stein, Jason L.; de la Torre-Ubieta, Luis
• 署名单位: University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California Los Angeles Medical Center; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California Los Angeles Medical Center; University of California System; University of California Los Angeles; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California Los Angeles Medical Center; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina School of Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Fudan University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aea1259
• 发表日期: 2026-04-23
• 页码: eaea1259
• 关键词: genome-wide association; NEURON SPECIFICATION; synaptic plasticity; alzheimers-disease; differentiation; chromatin; SATB2; neurogenesis; annotation; metabolism

摘要

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.