Chr21 protein-protein interactions: enrichment in proteins involved in intellectual disability, autism and late-onset Alzheimer’s disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201290 | GEO | 2022/07/18
REPOSITORIES: GEO
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Project description:Background: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. Results: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T-lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in brain cells. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites, implicating a mechanism involving altered transcription factor binding. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. Conclusions: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. Examination of methylation changes in two mouse models of Down syndrome with sub-chromosomal duplications, Dp(10)1Yey and Dp(16)1Yey, compared to one littermate wild type mouse using whole genome bisulfite sequencing.
2015-10-30 | E-GEOD-74505 | biostudies-arrayexpress
Project description:Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). However, the mechanisms by which T21 causes susceptibility to CHDs are poorly understood. Here, using a combination of human induced pluripotent stem cell (iPSC)-based model and Dp(16)1Yey/+ (Dp16) a mouse model of DS, we identified downregulation of canonical Wnt signaling that is caused by increased dosage of interferon (IFN) receptors encoded on chromosome 21 (HSA21) as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS as well as CHDs (DS/CHD iPSCs), and controls (control iPSCs) into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN pathways restored canonical WNT signaling and rescued defects during cardiac differentiation of DS/CHD iPSCs. Strikingly, treatment with an inhibitor of Janus kinase, which is activated by IFN receptor engagement normalized the canonical Wnt pathway and ameliorated CHDs in Dp16 embryos. Our findings provide new mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.
2023-06-28 | GSE217557 | GEO
Project description:Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that increased DYRK1A expression may be protective against TAM and ML-DS and that DYRK1A inhibition would not be a therapeutic option for GATA1s-associated leukemias.
2023-11-04 | GSE243702 | GEO
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
Project description:Down syndrome (DS), the most common human chromosomal disorder, is caused by trisomy 21. Recent studies show that the trisomic genes Dyrk1a and Kcnj6 play critical causative roles in DS cognitive deficits. Interestingly, an unexpected lack of improvement of hippocampal-dependent learning and memory deficits was observed when both Dyrk1a and Kcnj6 were normalized to diploidy in the DS mouse model, Dp(16)1/Yey (Dp16). In this study, we explored the molecular mechanisms underlying this phenomenon by using whole genome-wide hippocampal transcriptome analysis. In total, 142, 142, and 112 genes were found significantly differentially expressed in the Dp16, Dp16/Dyrk1aKO (Dyrk1a normalized) and Dp16;Dyrk1aKO/Kcnj6KO (Both Dyrk1a and Kcnj6 normalized) hippocampus, respectively, compared with the WT hippocampus. The majority of the common significantly differentially expressed genes (DEGs) were trisomic genes. Dyrk1a and Kcnj6 normalization mainly altered the expression of diploid genes. Normalizing Dyrk1a in the Dp16 hippocampus caused an overall downregulation of genes, whereas further Kcnj6 normalization caused an overall upregulation of genes. Both further rescuing effects and neutralizing effects were observed in Kcnj6 and Dyrk1a double-normalized mice compared with mice with Dyrk1a normalization alone.
2020-10-01 | GSE138468 | GEO
Project description:Microglia are the resident immune cells of the brain and have been implicated in mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by the presence of a supernumerary chromosome 21, which contains genes essential for the function of the immune system. Here, we investigated the presence of microglial alterations and their implication for cognitive impairment in the Dp(16) mouse model of DS. In the hippocampus of Dp(16) mice and individuals with DS, we found microglial morphology indicative of an activated state. Accordingly, we found increased levels of pro-inflammatory cytokines and altered interferon signaling in Dp(16) mice. In addition, Dp(16) mice showed decreased dendritic spine density and cognitive deficits. Remarkably, depletion of defective microglia by PLX3397 treatment or rescue of the microglia activated state by the commonly used anti-inflammatory drug acetaminophen fully rescued dendritic-spine density and cognitive deficits in Dp(16) mice. Our data suggest an involvement of microglia in the cognitive impairment of DS animals and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.
2020-09-22 | PXD015148 | Pride
Project description:Microglia are the resident immune cells of the brain and have been implicated in mechanisms essential for cognitive functions. Down syndrome (DS), the most frequent cause of genetic intellectual disability, is caused by the presence of a supernumerary chromosome 21, which contains genes essential for the function of the immune system. Here, we investigated the presence of microglial alterations and their implication for cognitive impairment in the Dp(16) mouse model of DS. In the hippocampus of Dp(16) mice and individuals with DS, we found microglial morphology indicative of an activated state. Accordingly, we found increased levels of pro-inflammatory cytokines and altered interferon signaling in Dp(16) mice. In addition, Dp(16) mice showed decreased dendritic spine density and cognitive deficits. Remarkably, depletion of defective microglia by PLX3397 treatment or rescue of the microglia activated state by the commonly used anti-inflammatory drug acetaminophen fully rescued dendritic-spine density and cognitive deficits in Dp(16) mice. Our data suggest an involvement of microglia in the cognitive impairment of DS animals and identify a new therapeutic approach for the potential rescue of cognitive disabilities in individuals with DS.
2020-09-22 | PXD015113 | Pride
Project description:Trisomy is a form of aneuploidy associated with embryonic and postnatal abnormalities in mammals. Understanding the underlying mechanisms involved in mutant phenotypes is broadly important and may lead to new strategies to treat clinical manifestations in individuals with trisomies, such as trisomy 21 (Down syndrome). While increased gene dosage effects due to a trisomy may account for the mutant phenotypes, there is also the possibility that phenotypic consequences of a trisomy can arise because of the presence of a freely segregating extra chromosome with its own centromere, i.e., a ‘free trisomy’ independent of gene dosage effects. Presently, there are no reports of attempts to functionally separate these two types of effects. To fill this gap, here we describe a strategy that employed two new mouse models of Down syndrome, Ts65Dn;Df(17)2Yey/+ and Dp(16)1Yey/Df(16)8Yey. Both models carry triplications of the same 103 human chromosome 21 gene orthologs; however, only Ts65Dn;Df(17)2Yey/+ mice carry a free trisomy. Comparative analysis of these two models revealed the gene dosage-independent effect of an extra chromosome at the phenotypic level for the first time, as reflected by impairments of Ts65Dn;Df(17)2Yey/+ males in T-maze tests when compared with Dp(16)1Yey/Df(16)8Yey males. Results from the transcriptomic analysis suggest the extra chromosome may play a major role in trisomy-associated expression alterations of disomic genes beyond gene dosage effects. This model system can now be used to deepen our mechanistic understanding of this common human aneuploidy and obtain new insights into the effects of free trisomies in other human diseases such as cancers.
2023-04-19 | GSE229563 | 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:The Dp(10)2Yey mouse carries a ~2.3 Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that makes it an essential model for aspects of Down syndrome (DS, trisomy 21). Specifically, these animals carry extra copies of Mmu10 genes that are homologous to those on human chromosome 21 (Hsa21). Here, we report spatial memory impairment and anxiety-like behaviour in this model alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey DS mice showed impaired spatial alternation associated with increased ripple activity in mPFC during the period of memory consolidation, and reduced mobility in a novel environment accompanied by reduced theta-gamma phase-amplitude coupling in HPC. Finally, we found alterations in the number of interneuron subtypes in mPFC and HPC that may contribute to the observed phenotypes and highlight potential approaches to ameliorate the effects of human trisomy 21.
2023-02-22 | GSE214273 | GEO