Integrative multi-omics analysis reveals conserved cell-projection deficits in human Down syndrome brains [smallRNAseq]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE221130 | GEO | 2024/06/02
REPOSITORIES: GEO
Similar Datasets
Project description:Down syndrome (DS) is the most common genetic cause of cognitive disability. However, it is largely unclear how the triplication of a small gene subset may impinge on diverse aspects of DS brain physio-pathology. Here, we took a multi-omics approach and simultaneously analyze by RNA-seq and proteomics the expression signature of two diverse regions of human postmortem DS brains. We found that the overexpression of triplicated genes triggered global expression dysregulations differentially affecting transcripts, miRNA and proteins involved in both known and novel candidate pathways. Among the latter, we observed alteration of RNA splicing in DS brains specifically altering the expression of genes involved in cytoskeleton and axonal dynamics. Accordingly, we found alteration in axonal polarization in neurons from both DS human induced-pluripotent-stem cells and mice. Thus, our study provides an integrated multi-layer expression database capable of identifying new potential targets to possibly aid design future clinical interventions in DS.
2024-06-02 | GSE221178 | GEO
Project description:Down syndrome (DS) is the most common genetic cause of cognitive disability. However, it is largely unclear how triplication of a small gene subset may impinge on diverse aspects of DS brain physiopathology. Here, we took a multi-omic approach and simultaneously analyzed by RNA-seq and proteomics the expression signatures of two diverse regions of human postmortem DS brains. We found that the overexpression of triplicated genes triggered global expression dysregulation, differentially affecting transcripts, miRNAs, and proteins involved in both known and novel biological candidate pathways. Among the latter, we observed an alteration in RNA splicing, specifically modulating the expression of genes involved in cytoskeleton and axonal dynamics in DS brains. Accordingly, we found an alteration in axonal polarization in neurons from DS human iPSCs and mice. Thus, our study provides an integrated multilayer expression database capable of identifying new potential targets to aid in designing future clinical interventions for DS.
2024-06-02 | GSE221179 | GEO
Project description:Down syndrome (DS) is a neurodevelopmental disorder caused by an extra copy of human chromosome 21 (HSA21). People with Down syndrome have poor motor skills and speech, impaired adaptive behavior, and cognition deficits. (Carlesimo et al., 1997; Contestabile et al., 2010; Roizen and Patterson, 2003; Sherman et al., 2007; Vicari et al., 2000). At the brain anatomical level, DS is characterized by structural deficiencies in diverse regions. These deficits include hippocampal and cortical growth reduction, abnormal lamination and differentiation of neurons, decreased dendritic branching and spine density, and abnormal synaptic plasticity (Kazemi et al., 2016; Rachidi and Lopes, 2011). Even though the genetic cause of DS was discovered in 1959 (Megarbane et al., 2009), we still do not know the precise mechanisms by which triplication of HSA21 genes leads to neuroanatomical and neurobehavioral phenotypes in DS individuals. Moreover, a fundamental question in DS is to discover the impact of the triplication of chromosome 21 on the global expression regulation of non-triplicated genes (Letourneau et al., 2014) and how these profound changes at the genetic level translate to phenotypic changes in DS individuals. Finally, drug treatments targeting various putative molecular pathways are effective in rescuing cognition in DS animals. Nevertheless, while the preclinical studies performed in diverse mouse models of DS have reported improvement in cognitive deficits, the same drugs have failed to replicate all the good and promising effects when administered to people with DS during clinical trials (Rueda et al., 2020). Therefore, there is a notable need in strongly extending our understanding of DS in humans. Global gene expression analysis at the mRNA or protein level with different techniques have reported interesting findings on disparate DS-derived samples (fibroblasts, circulating immune cells, and amniocytes) (Guedj et al., 2016; Stamoulis et al., 2019; Waugh et al., 2019; Lanzillotta et al., 2020; Liu et al., 2017. Liu et al., 2018; Sommer et al., 2008) or iPSC-derived neurons obtained from DS individuals (Gonzales et al., 2018; Huo et al., 2018; Sobel et al., 2019). However, only a few studies have directly assessed global mRNA dysregulation in the adult DS brains by microarray hybridization (Lockstone et al., 2007; Olmos-Serrano et al., 2016). Although the latter studies have provided interesting information about the significant cellular pathways altered in trisomy, they lacked the depth, sensitivity, and isoform specificity that characterize modern gene expression analysis by next-generation sequencing (NGS). In this regard, another study used single-nucleus RNA sequencing (snRNA-seq) to profile aging DS brains (Palmer et al., 2021). Although this cutting-edge technique can deliver high-level information for the characterization of cellular diversity in brain tissues, this comes at the cost of profiling less number of genes (Bakken et al., 2018) and the possibility of missing the specific signature of important pathological processes (Thrupp et al., 2020). Moreover, none of these studies addressed the other side of the coin, assessing the corresponding changes in protein expression. In fact, the question of how well the transcriptome expression profiles match with those at the protein level remains largely unanswered. Large-scale analysis of transcriptome and proteome of the human brain would therefore provide a more comprehensive data-driven approach to identify dysregulated biological processes or genes/proteins co-expression networks as drivers of disease pathogenesis and prioritize the development of corresponding therapeutic interventions. Here, we took a multi-level data acquisition and interpretation approach to integrate in-depth transcriptomics and proteomics data in parallel from the same set of human brain samples to identify dysregulated expression networks in DS, a complex and multigenic neurodevelopmental disorder. We also provide unprecedented evidence of changes in mRNA transcript (isoform) expression, and to our knowledge, a first integrative analysis to identify alternative splicing, RNA binding proteins, and miRNAs as crucial intermediate regulatory steps in DS. Our data provide molecular information signatures that consistently repeat at gene, transcript, and protein levels and may function as critical players in DS pathophysiology. In particular, our multi-level data pinpoint to alteration in cell projection genes that translate into defects in axon and dendrites formation, which we find in DS iPSC derived neurons and primary hippocampal culture from a murine DS model.
2024-06-03 | PXD038791 | Pride
Project description:Cortical organoids generated from mESC from a Down Syndrome (DS) mouse model (Ts65Dn) were dissociated for single cell sequencing to understand whether differential gene expression in DS brains affects cell diversity and how the molecular events that control the development of these diverse types of neocortical neurons are affected by the trisomy. These results were generated in parallel to a single cell experiment in forebrain fetal tissue from WT and Ts65Dn mice.
2023-03-15 | E-MTAB-12827 | biostudies-arrayexpress
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.
2022-09-22 | GSE151255 | GEO
Project description:A major challenge in Down syndrome (DS) is to understand how the extra-dose of functional chromosome 21 (HSA21) genetic elements can impact on the tissue-specific transcriptome to contribute to phenotypic alterations. MiRNAs are post-transcriptional modulators with genome-wide regulatory effects. Five microRNAs have been identified in HSA21 that are present in triple copy in DS individuals. Interestingly, in the Ts65Dn mouse model of DS two of these miRNAs, miR-155 and miR-802, are also triplicated resulting in its overexpression. In the current work, we have developed a lentiviral miRNA-sponge genetic strategy for miR-155 and miR-802 (Lv-miR155-802T) to identify novel mRNA targets involved in hippocampal function. Hippocampal injection of the lentiviral sponge in Ts65Dn mice reduced miR-155 and miR-802 overexpression. Noticeable lentiviral sponge rescued the expression of the miRNA predicted targets showing the potential of the strategy to identify miRNA dosage-sensitive genes with potential involvement in DS-hippocampal phenotypes.
2015-05-16 | GSE68074 | GEO
Project description:To understand the molecular basis of Down syndrome pathogenesis, we performed a transcriptome analysis of nine different tissues in Ts65Dn, an established mouse model of human trisomy 21. Ts65Dn mice have segmental trisomy of mouse chromosome 16 with ca. 128 genes at dosage imbalance (Reeves et al. 1995). The Ts65Dn mouse is widely used as a model for studies of DS because it is at dosage imbalance for the orthologs of about half the 284 Chr21 genes. Ts65Dn mice have several features that directly parallel developmental anomalies of DS. We compare here the expression of 136 mouse orthologs of Chr21 genes, 77 of which are triplicated in Ts65Dn, in trisomic and euploid mice. <br> <br> We designed a mouse cDNA expression array interrogating 136 mmu21 genes. RNA pools from four adult male Ts65Dn mice and four male euploid littermates were prepared from cortex and dissected from three to four month-old mice. Directly labeled first strand cDNA probes from nine different tissues were hybridized to the arrays in replicated hybridizations. A total of 446 genes that are not triplicated in Ts65Dn mice served as controls. These included 62 mmu21 genes from MMU10, MMU17, and non-triplicated portions of MMU16, plus 384 randomly distributed mouse cDNAs from the Unigene collection.
2004-04-23 | E-MEXP-102 | biostudies-arrayexpress
Project description:Integrative multi-omics analysis reveals conserved cell-projection deficits in human Down syndrome brains [smallRNAseq]
| PRJNA913024 | ENA
Project description:Trisomy 21 (Ts21) or Down syndrome (DS) is the most common genetic cause of intellectual disability. To investigate the consequences of Ts21 on human brain development, we have systematically analyzed the transcriptome of dorsolateral prefrontal cortex (DFC) and cerebellar cortex (CBC) using exon array mapping in DS and matched euploid control brains spanning from prenatal development to adulthood. We identify hundreds of differentially expressed (DEX) genes in the DS brains, many of which exhibit temporal changes in expression over the lifespan. To gain insight into how these DEX genes may cause specific DS phenotypes, we identified functional modules of co-expressed genes using several different bioinformatics approaches, including WGCNA and gene ontology analysis. A module comprised of genes associated with myelination, including those dynamically expressed over the course of oligodendrocyte development, was amongst those with the great levels of differential gene expression. Using Ts65Dn mouse line, the most common rodent model of DS, w e observed significant and novel defects in oligodendrocyte maturation and myelin ultrastructure; establishing a correlative proof-of-principle implicating myelin dysgenesis in DS. Thus, examination of the spatio-temporal transcriptome predicts specific cellular and functional events in the DS brain and is an outstanding resource for determining putative mechanisms involved in the neuropathology of DS.
2016-01-20 | GSE59630 | GEO
Project description:Almost all individuals with Down Syndrome (DS) develop Alzheimer’s disease (AD) by mid to late life. However, the degree to which AD in DS shares pathological changes with sporadic late-onset AD (LOAD) and autosomal dominant AD (ADAD) beyond core AD biomarkers such as amyloid-β (Aβ) and tau is unknown. Here, we used proteomics of cerebrospinal fluid from individuals with DS (n=229) in the Down Alzheimer Barcelona Neuroimaging Initiative (DABNI) cohort to assess the evolution of AD pathophysiology from asymptomatic to dementia stages and compared the proteomic biomarker changes in DS to those observed in LOAD and ADAD. Although many proteomic alterations were shared across DS, LOAD, and ADAD, DS demonstrated more severe changes in immune-related proteins, extracellular matrix pathways, and plasma proteins likely related to blood-brain barrier dysfunction compared to LOAD. These changes were present in young adults with DS prior to the onset of Aβ or tau pathology, suggesting they are associated with trisomy 21 and may serve as risk factors for DSAD. DSAD showed an earlier increase in markers of axonal and white matter pathology and earlier changes in markers potentially associated with cerebral amyloid angiopathy compared to ADAD. The unique features of DSAD may have important implications for treatment strategies in this population.
2025-07-08 | PXD064699 | Pride