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Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - Neural Cells in vitro Basic Characterisation Bulk RNA-seq Dataset

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305135 | GEO | 2025/12/23

REPOSITORIES: GEO

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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)

Project description: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.

2025-12-23 | GSE305132 | GEO

Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - Fetal Cortex Bulk RNA-seq Dataset

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Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - Fetal Cortex Multiome Dataset

Project description:Down syndrome, caused by an extra copy of chromosome 21, is the most common genetic form of intellectual disability affecting up to 1 in 700 live births1-3. Yet, it remains unclear how the increased dosage of ~200 protein-coding genes on chromosome 21 affects brain development, particularly in the cerebral cortex—the area central to higher-level cognitive functions4-7. Here we generated a single-cell transcriptome and chromatin accessibility atlas from 30 human fetal cortical samples at mid gestation (10-20 weeks after conception), a critical period of cortical development8. We discovered an early global transcriptional network disruption, subtly altering ~600 genes involved in neural development and function, mostly in excitatory neurons accompanied by a significant reduction in RORB/FOXP1 expressing excitatory neurons. Multimodal network analyses predicted the chromosome 21 transcription factors BACH1, PKNOX1, and GABPA as key regulatory hubs controlling dozens of genes genetically linked to intellectual disability. Antisense-mediated normalization of the increased activity of these transcription factors in stem-cell-derived neural cells in vitro, which partially recapitulated molecular changes in the Down syndrome cortex, rescued expression of several of these predicted intellectual disability-associated targets. Finally, a humanized in vivo model replicates key molecular features of Down syndrome not recapitulated in neural cells in vitro. This resource defines the gene-regulatory landscape of the developing human cortex in Down syndrome, revealing early molecular and cellular signatures and candidate therapeutic targets, along with a human in vivo experimental platform for their preclinical testing.

2025-12-23 | GSE305146 | GEO

Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - iPSC-derived Neural Xenografts Multiome Dataset

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Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - iPSC-derived Neural Xenografts snRNA-seq Dataset

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Correction of cognitive deficits in mouse models of Down syndrome by pharmacological inhibitor of DYRK1A

Project description:Down Syndrome (DS) results from the trisomy of human chromosome 21 (HSA21). It is still the most frequent intellectual disability, affecting 1 newborn per 700 births. Among candidate genes explaining intellectual disabilities seen in DS patients, the dual specificity tyrosine-phosphorylation regulated kinase 1A, DYRK1A, is located in the DS critical region of chromosome 21. DYRK1A has become a major screening target for the development of selective and potent pharmacological inhibitors. We here investigated the effects of a relatively selective DYRK1A inhibitor, Leucettine 41 (hereafter L41) in three different trisomic mouse models with increasing genetic complexity, Tg(Dyrk1a), Ts65Dn and Dp1Yey. Leucettines are derived from the marine sponge alkaloid Leucettamine B.

2018-10-17 | PXD008419 | Pride

A transcriptome analysis study with the focus on the role of long non-coding RNAs in Down syndrome subjects

Project description:Down syndrome (DS) results from trisomy of chromosome 21 and is the most common genetic cause of intellectual disability (ID). A wide range of comorbidities have been described in DS, such as ID, muscle weakness, hypotonia, congenital heart disease and autoimmune diseases. The pathogenetic mechanisms that are responsible for developing these comorbidities are still far from being understood. It was hypothesized that dosage imbalance on chromosome 21 as a whole disrupts diverse developmental pathways whereas another hypothesis suggests that dosage increase for specific genes on chromosome 21 contributes directly to different aspects of the phenotype in DS. The present study explored mRNAs and lncRNAs expression by using the next generation sequencing analysis (NGS) and the quantitative real-time PCR (qRT-PCR) assay for the confirmation of the NGS results, followed by functional analysis of the results. The enrichment analysis of the results obtained revealed various pathways in which differentially expressed genes are involved. Developmental disorders play a crucial role in the phenotype of people with Down syndrome with particular attention to intellectual developmental disorders.

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Project description:Down syndrome, caused by trisomy 21, is a complex developmental disorder associated with intellectual disability and reduced growth of multiple organs. Structural pathologies are present at birth, reflecting embryonic origins. A fundamental unanswered question is how an extra copy of human chromosome 21 contributes to organ-specific pathologies that characterize individuals with Down syndrome. Relevant to the hallmark intellectual disability in Down syndrome, how does trisomy 21 affect neural development? We tested the hypothesis that trisomy 21 exerts effects on human neural development as early as neural induction. Bulk RNA sequencing was performed on isogenic trisomy 21 and euploid human induced pluripotent stem cells (iPSCs) at successive stages of neural induction: embryoid bodies at Day 6, early neuroectoderm at Day 10, and differentiated neuroectoderm at Day 17. Gene expression analysis revealed over 1,300 differentially expressed genes in trisomy 21 cells along the differentiation pathway compared to euploid controls. Less than 5% of the gene expression changes included upregulated chromosome 21 encoded genes at every timepoint. Genes involved in specific growth factor signaling pathways (Wnt and Notch), metabolism (including interferon response and oxidative stress), and extracellular matrix were altered in trisomy 21 cells. Further analysis revealed heterochronic expression of genes. This comprehensive analysis reveals that trisomy 21 impacts discrete developmental pathways at the earliest stages of neural development. Further, the results suggest that metabolic dysfunction arises early in embryogenesis in trisomy 21 and may thus affect development and function more broadly.

2024-01-31 | GSE247990 | GEO

Rescue of Down syndrome related deficits by Brwd1 copy number restoration

Project description:Trisomy 21 [Down syndrome/DS] is the most common genetic cause of intellectual disability worldwide. Despite much progress in the genetic characterization of DS, the genes encoded from chromosome 21 (HSA21) that directly contribute to intellectual disability remain incompletely understood. Here, we found that a largely uncharacterized chromatin effector protein, BRWD1, is triplicated in DS neurons and brain of trisomic mice. We demonstrated that selective copy number restoration of Brwd1 in DS animals rescues transcriptional, synaptic and cognitive deficits. We showed that Brwd1 binds to the neuronal BAF chromatin remodeling complex, and that such interactions promote BAF’s genomic mistargeting in DS-like brain. Brwd1 renormalization in trisomic animals rescues these aberrant chromatin events. These findings thus establish BRWD1 as a critical epigenomic mediator of DS related phenotypes.

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Proteome analysis in the TcMAC21 mouse model of Down syndrome

Project description:Down syndrome (DS) results from trisomy of human chromosome 21 (HSA21), and DS research has been greatly advanced by the use of mouse models. We previously generated a humanized mouse model of DS, TcMAC21, which carries the long arm of HSA21. These mice exhibit learning and memory deficits, and may reproduce neurodevelopmental alterations observed in humans with DS. Here we performed histologic studies of the TcMAC21 forebrain from embryonic to adult stages. The TcMAC21 neocortex showed reduced proliferation of neural progenitors and delayed neurogenesis. These abnormalities were associated with a smaller number of projection neurons and interneurons. Further, (phospho-)proteomic analysis of adult TcMAC21 cortex revealed alterations in the phosphorylation levels of a series of synaptic proteins. The TcMAC21 mouse model shows similar brain development abnormalities as DS, and will be a valuable mode to investigate prenatal and postnatal causes of intellectual disability in humans with DS.

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