Genome-wide expression analysis in Down syndrome: insight into immunodeficiency
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE35665 | GEO | 2012/02/10
SECONDARY ACCESSION(S): PRJNA152435
REPOSITORIES: GEO
Similar Datasets
Project description:Down syndrome (DS) is caused by triplication of Human chromosome 21 (Hsa21) and associated with an array of deleterious phenotypes, including mental retardation, heart defects and immunodeficiency. Spatio-temporal patterns of genome-wide expression are critical to the understanding of DS. We used a Human Exon microarray to characterize gene expression in peripheral blood cells derived from DS and control individuals from two age groups: neonate (N) and child (C). A total of 174 transcript clusters (gene-level) with eight located on Hsa21 in N group and 383 transcript clusters including 57 on Hsa21 in C group were significantly dysregulated in DS individuals. Except for 22 commonly dysregulated genes in the two groups, the remaining dysregulated genes were different between N and C groups, reflecting temporally dynamic variation in gene expression in DS. Dramatically fewer dysregulated Hsa21 genes in N group than those in C group suggested that triplication of Hsa21 per se induces a moderate deregulation at early developmental stages. Further functional analysis revealed that the dysregulated genes in DS were significantly enriched in two KEGG pathways in N group and six pathways in C group. These pathways included leukocyte trans-endothelial migration, B cell receptor signaling pathway and primary immunodeficiency, etc., which causally implicated dysfunctional immunity in DS. Our results provided a comprehensive picture of expression patterns of DS at the two developmental stages and point towards candidate genes and molecular pathways potentially associated with the immune dysfunction in DS. All 37 samples, including 15 DS patients and 22 control individuals were analysized and divided into two age-matched groups: N group (5 DS versus 7 control individuals, age: 3 days to 38 days) and C group (10 DS versus 15 control individuals, age: 1 year to 13 years). N group includes DS (D11-D15) and Control (C16-C22), and C group includes DS (D1-D10) and Control (C1-C15).
2012-02-10 | E-GEOD-35665 | biostudies-arrayexpress
Project description:Down syndrome is the main genetic cause of intellectual disability and is due to triplication of human chromosome 21 (HSA21). Green tea extracts containing epigallocatechin-3-gallate (green tea) improve cognition both in mouse models and individuals with Down syndrome. We here analyzed the proteome and phosphoproteome alterations in a Down syndrome mouse model, the partial trisomic Ts65Dn mice, and the effect produced by the green tea extract and environmental enrichment (EE). Trisomic hippocampi presented a dysregulated proteome, especially when looking at the phosphorylation level in cognitive-related categories (synaptic proteins, neuronal projection, neuron development, microtubule), and GTPases/kinase activity and chromatin related categories. Green tea, EE, and their phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function and phosphorylation, and autophagy to exert many of its beneficial biological actions Of interest for DS, it inhibits the activity of the Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase 1A (DYRK1A), a DS candidate gene located in the 21q22.2 human chromosome region4,5. Previous work from our group showed that EGCG partially rescues the effects of overexpression of a DS candidate gene, DYRK1A, on the proteome and phosphoproteome of the hippocampus of TgDyrk1A mice6. However, the extent to which these mechanisms apply to a trisomy scenario is unknown. To get insight in these mechanisms we analyzed changes in protein abundances and phosphorylation in Ts65Dn mice, and their disomic counterparts in baseline conditions and upon three treatments known to improve cognition in Ts65Dn: i) green tea extract containing EGCG, ii) environmental enrichment (EE), and iii) their combination.
2020-10-13 | PXD018515 | Pride
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:Down syndrome (DS) is the most prevalent genetic abnormality, occurring in ~1/700 live births caused by triplication of human chromosome 21 (HSA21). DS individuals have a multitude of phenotypic changes in peripheral systems and most notably, are cognitively impaired, with deficits in learning, language and memory acquisition and consolidation. Further, individuals with DS develop Alzheimer’s disease (AD) pathology during early middle-age (mid-30’s), although the underlying mechanism(s) driving this pathology onset are not well understood. Contributing to cognitive impairment in DS, morphological deficits are present in cortical lamination and distribution, with Layer III (L3) and Layer V (L5) pyramidal neurons showing reduced proliferation and a disorganized laminar structure. As such, examining cortical L3 and L5 pyramidal neurons in DS individuals with AD pathology may elucidate alternate driver mechanisms of disease onset. We examined DS and age-matched control (CTR) brains from individuals without intellectual disabilities or dementia using postmortem frontal cortex (BA9) via single population low input RNA-sequencing. We specifically targeted L3 and L5 pyramidal neurons to understand circuitry-based alterations in DS/AD individuals to elucidate mechanistic drivers of disease pathology. We show convergent and divergent gene expression changes in L3 and L5 pyramidal neurons which may underlie cognitive deficits and degenerative pathology associated with aging in the DS brain. We pinpoint alterations in HSA21 gene expression as well as a multitude of convergent differentially expressed genes (DEGs) and relevant pathways via bioinformatic inquiry in the DS brains that underlie mechanisms of degeneration. Distinctly, convergent gene expression reveals a neurotoxic phenotype, with multiple canonical pathways of dysregulation and disease functions linked to the convergent DEGs, including downregulation of the CLEAR signaling pathway and significantly increased activation of the neuroinflammation signaling pathway. We identify several target genes including mitogen activated protein kinase 1 and 3 (MAPK1/3), calcium voltage-gated channel subunit alpha1 A (CACNA1A) and superoxide dismutase 1 (SOD1), which exhibit overlap in multiple pathways and disease functions and/or display dysfunctional protein-protein network interactions for further examination. Novel targets identified by our single population approach in L3 and L5 pyramidal neurons may be drivers of the disease mechanism and therefore may be therapeutic candidates for amelioration of degenerative pathology that targets memory and executive function circuits in DS/AD.
2024-08-07 | GSE251939 | GEO
Project description:To identify the genes, which led to the augmented hematopoiesis in DS-iPS cells, we performed gene expression profiling of D12-DS-iPS cells (DS-iPS-T32, DS-iPS-T33 and DS-iPS-T31) and control hiPS cells (253G1, 253G4 and A31) generated by 3 factors. In the comparison of gene expression levels in each DS-iPS cell clone with the average of these in control iPS cell clones, 972 genes showed more than 2-fold increased expression, and 1118 genes showed decreased expression in all DS-iPS cell clones. Among these upregulated genes, 61 genes including GATA1 were involved in hematopoiesis-related genes according to Ingenuity Pathways Analysis (IPA). Among the above 2-fold more upregulated genes in DS-iPS cells, 18 genes were on Hsa21. The expression of RUNX1 on Hsa21, a hematopoiesis-related gene, was significantly upregulated in DS-iPS cells. The high expressions of GATA1 and RUNX1 were also identified in 4-factor DS-iPS cells.
2011-11-29 | GSE33911 | GEO
Project description:To identify the genes, which led to the augmented hematopoiesis in DS-iPS cells, we performed gene expression profiling of D12-DS-iPS cells (DS-iPS-T32, DS-iPS-T33 and DS-iPS-T31) and control hiPS cells (253G1, 253G4 and A31) generated by 3 factors. In the comparison of gene expression levels in each DS-iPS cell clone with the average of these in control iPS cell clones, 972 genes showed more than 2-fold increased expression, and 1118 genes showed decreased expression in all DS-iPS cell clones. Among these upregulated genes, 61 genes including GATA1 were involved in hematopoiesis-related genes according to Ingenuity Pathways Analysis (IPA). Among the above 2-fold more upregulated genes in DS-iPS cells, 18 genes were on Hsa21. The expression of RUNX1 on Hsa21, a hematopoiesis-related gene, was significantly upregulated in DS-iPS cells. The high expressions of GATA1 and RUNX1 were also identified in 4-factor DS-iPS cells. Gene expression in blood cells differentiated from human induced pluripotent stem cells derived from patients with Down syndrome and healthy donor was measured in 12 days after induction of differentiation. Eight cell lines were used.
2011-11-29 | E-GEOD-33911 | biostudies-arrayexpress
Project description:In this study we performed a systematic analysis of the non-coding RNA (ncRNA) transcriptomes of the Down Syndrome (DS) developing hippocampus using the DS mouse model Dp16(1)Yey. DS, caused by the trisomy of chromosome 21 (HSA21) is the most frequent human chromosomal disorder. Hippocampal-dependent learning and memory impairment is one of the most significant deficits of DS. ncRNAs: microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) have been increasingly revealed to be participating in various biological activities, especially in the brain development and neuronal functions. This study provides a map of the dysregulated lncRNAs and circRNAs in the DS developing hippocampus for the first time.
2020-05-31 | GSE120801 | 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:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
2023-05-10 | PXD030616 | Pride
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.
2023-10-23 | PXD044343 | Pride