CRLF2 overexpression in B cells from the Dp16 model of Down syndrome
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB43591 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR8314600_1.fastq.gz | Fastqsanger.gz | |||
| ERR8314600_2.fastq.gz | Fastqsanger.gz | |||
| ERR8314601_1.fastq.gz | Fastqsanger.gz | |||
| ERR8314601_2.fastq.gz | Fastqsanger.gz | |||
| ERR8314602_1.fastq.gz | Fastqsanger.gz |
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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:Recent epidemiological studies suggest that individuals with Down syndrome are more susceptible to SARS-CoV-2 infection and have higher rates of hospitalization and mortality than the general population. However, the main drivers behind these disparate health outcomes remain unknown. Herein we performed experimental infections with SARS-CoV-2 in a well-established mouse model of Down syndrome, Dp(16)1Yey/+;Tg(K18-ACE2)2Prlmn/+ (abbreviated as Dp16;ACE2). We observed similar SARS-CoV-2 replication kinetics and dissemination in the primary and secondary organs between mice with and without Down syndrome (i.e., Dp16;ACE2 and ACE2), suggesting that both groups have similar susceptibilities to SARS-CoV-2 infection. However, Down syndrome mice exhibited more severe disease as defined by clinical features including symptoms, weight loss, pulmonary function, and survival of mice. We found that increased disease severity in Down syndrome mice could not be attributed solely to increased infectivity or a more dramatic pro-inflammatory response to infection. Rather, results from RNA sequencing suggested that differences in expression of genes from other physiological pathways such as deficient oxidative phosphorylation, cardiopulmonary dysfunction and deficient mucociliary clearance in the lungs may also contribute to heightened disease severity and mortality in Down syndrome mice following SARS-CoV-2 infection.
2024-03-04 | GSE260583 | GEO
Project description:Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 35 non-Down syndrome (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression, and methylation analyses. We report novel deletions within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 12 DS (24%) and only a single NDS case (3%) (Fisher’s exact p = 0.013). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters, and enrichment of highly methylated genes for specific pathways and transcription factor binding motifs. Gene expression profiling identified CRLF2 overexpression in nearly half DS-ALL cases, and supervised analysis identified an associated 39-gene signature. However, no expression signature was identified for DS-ALL overall, nor for histone status, suggesting that DS-ALL constitutes several, heterogeneous molecular entities. Characterization of pathways associated with histone deletions and high CRLF2 expression may identify opportunities for novel targeted interventions. This SuperSeries is composed of the SubSeries listed below.
2011-07-12 | GSE21094 | GEO
Project description:Chromosomal aneuploidy and translocations are hallmarks of acute lymphoblastic leukemia (ALL), but many patients lack a recurring chromosomal alteration. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that results in the expression of a novel fusion that juxtaposes the first non-coding exon of P2RY8 to the coding region of the CRLF2 (cytokine receptor like factor 2, or thymic stromal lymphopoietin receptor) gene. The P2RY8-CRLF2 fusion was identified in 7% of B-ALL cases, and was very common in ALL associated with Down syndrome (55% of cases) and was associated with the presence of JAK mutations. The P2RY8-CRLF2 fusion results in increased expression of CRLF2, a lymphoid signaling molecule that forms a heterodimeric complex with interleukin receptor 7 alpha. These findings identify a novel recurring chromosomal alteration in B-ALL, and suggest that perturbed CRLF2-mediated signaling is a key event in leukemogenesis in these cases. Profiling of tumor acquired DNA copy number alterations in 2 patients with Down syndrome associated B-progenitor acute lymphoblastic leukemia. Matched tumor and normal DNA was used for each array hybridization in each case.
2009-10-18 | E-GEOD-16724 | biostudies-arrayexpress
Project description:Down syndrome (DS), a genetic condition leading to intellectual disability, is characterized by triplication of human chromosome 21. Neuropathological hallmarks of DS include abnormal central nervous system development that manifests during gestation and extends throughout life. As a result, newborns and adults with DS exhibit cognitive and motor deficits and fail to meet typical developmental and lack independent life skills. A critical outstanding question is how DS-specific prenatal and postnatal phenotypes are recapitulated in different mouse models. To begin answering this question, we developed a life span approach to directly compare differences in embryonic brain development, cellularity, gene expression, neonatal and adult behavior behavior in three cytogenetically distinct mouse models of DS—Ts1Cje, Ts65Dn and Dp16/1Yey (Dp16). In the last two decades multiple therapeutic trials have been attempted to improve cognition in humans with DS but the results of these interventions lacked efficacy despide their succes in the Ts65Dn mouse model of DS. To better understand how phenotypic changes in humans in DS are recapitulated in different mouse models, we copared embryonic brain development and gene expression, perinatal behavior and brain excitatoty/inhibitory cell distribution, and adult behavior and gene expression in the Dp16, Ts65Dn and Ts1Cje mouse models of DS. The objectives of this study were to determine the best model(s) for prenatal and postnatal therapeutic trials and to identify treatment endpoints that can be used to evaluate the fficacy of these therapies prior to human clinical trials. Our data showed that, at embryonic day 15.5, Ts65Dn mice are the most profoundly and consistently affected with respect to somatic growth, brain morphogenesis, and neurogenesis compared to Ts1Cje and Dp16 embryos. However, gene expression results show that both Ts65Dn and Ts1Cje embryonic forebrains have a relatively high number of differentially expressed genes compared to Dp16, with little overlap in gene identities and genomic distribution observed among these models. Additionally, postnatal histological analyses show varying degrees of cell population and brain histogenesis abnormalities among the three strains. Behavioral testing also highlights differences among the models in their ability to meet various developmental milestones. At adulthood, Ts65Dn and Ts1Cje showed hyperactive behavior in the open field test but not Dp16 mice. In the fear conditioning test, all three strains showed lower freezing versus eupploid mice; Dp16 were the most severely affected. In the Morris water maze, Ts65Dn showed significant delays in the hidden platform, probe and reversal trials. Dp16 mice showed milder deficits in the hidden platform trial but severe deficits in reversal. Ts1Cje mice had no spatial memory deficits. In the rotarod test, Dp16 performed poorly in fixed and accelerating speed trials, while Ts1Cje was only abnormal at high speeds. Ts65Dn rotarod performance was unaffected. Compared to euploid, Ts65Dn had a higher number of differentially expressed (DEX) genes in cortex and cerebellum, while Ts1Cje had more DEX genes in hippocampus and cerebellum. Dp16 had the lowest number of DEX genes in all regions analyzed. Pathway analyses highlighted commonly dysregulated pathways, including G-protein signaling, oxidative stress, interferon signaling, glycosylation and disulfide bonds.
2017-05-23 | GSE99135 | GEO
Project description:Whole genome non-coding RNA profiling of the developing hippocampus of the Down syndrome mouse model Dp16(1)Yey
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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:Chromosomal aneuploidy and translocations are hallmarks of acute lymphoblastic leukemia (ALL), but many patients lack a recurring chromosomal alteration. Here we report a recurring interstitial deletion of the pseudoautosomal region 1 of chromosomes X and Y in B-progenitor ALL that results in the expression of a novel fusion that juxtaposes the first non-coding exon of P2RY8 to the coding region of the CRLF2 (cytokine receptor like factor 2, or thymic stromal lymphopoietin receptor) gene. The P2RY8-CRLF2 fusion was identified in 7% of B-ALL cases, and was very common in ALL associated with Down syndrome (55% of cases) and was associated with the presence of JAK mutations. The P2RY8-CRLF2 fusion results in increased expression of CRLF2, a lymphoid signaling molecule that forms a heterodimeric complex with interleukin receptor 7 alpha. These findings identify a novel recurring chromosomal alteration in B-ALL, and suggest that perturbed CRLF2-mediated signaling is a key event in leukemogenesis in these cases.
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Project description:Transcriptome study of MX1 overexpression on down syndrome derived aminocytes(DSACs)
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