Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - Neural Progenitors in vitro - Treatment with Antisense Oligonucleotides for PKNOX1, BACH1 and GABPA (Bulk RNA-seq Dataset)

Down syndrome, caused by an extra copy of chromosome 21, is the most common genetic form of intellectual disability, which affects up to 1 in 700 live births. Yet, how increased dosage of the ~200 protein-coding genes on human chromosome 21 affects cortical development and function remains unclear. Here we generated a single-cell transcriptome and chromatin accessibility atlas of the human foetal cortex at mid gestation (11-20 weeks after conception), a critical period of cortical development. We uncovered an early global transcriptional network disruption, subtly altering ~1000 genes involved in neural development and function primarily in excitatory neurons. These changes reflected clinical phenotypes like intellectual disability and epilepsy, were accompanied by a significant reduction in layer 4 neurons, and were driven by a network of transcription factors including chromosome 21 genes BACH1, PKNOX1, and GABPA. Finally, a xenograft model replicates key molecular features, offering an experimental platform for validating new therapeutic targets. This resource defines the gene-regulatory landscape of the developing human cortex in Down syndrome, revealing the earliest known molecular and cellular signatures of its neurological manifestations and novel candidate targets for therapeutic interventions. Overall design: We performed bulk RNA-seq of from iPSC-derived human neural progenitors (iNPCs) in vitro from an individual with DS and from isogenic control iPSCs (CON, normal diploid karyotype; C13(DS) and C9 (CON) from Murray et al., 2015 and Alic et al. 2021, generated and provided by Dean Nizetic and Ivan Alic). Progenitors were treated with antisense oligonucleotides (ASOs) to downregulate the transcription factors PKNOX1, BACH1 and GABPA, to assess consequences for the regulation of predicted downstream target genes. For ASO designs see related manuscript.