Rescue of Down syndrome related deficits by Brwd1 copy number restoration in Ts65Dn mice
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ABSTRACT:
PROVIDER: PRJNA863848 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20720500_1.fastq.gz | Fastqsanger.gz | |||
| SRR20720500_2.fastq.gz | Fastqsanger.gz | |||
| SRR20720501_1.fastq.gz | Fastqsanger.gz | |||
| SRR20720501_2.fastq.gz | Fastqsanger.gz | |||
| SRR20720502_1.fastq.gz | Fastqsanger.gz |
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Project description:With an astounding incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in Down syndrome neurons and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.
2022-09-21 | GSE210117 | GEO
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:Rescue of Down syndrome related deficits by Brwd1 copy number restoration
| PRJNA635321 | ENA
Project description:Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. We demonstrate in small pre-B cells, that the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 differentially regulated over 7000 genes including repressing proliferative and inducing differentiation programs. However, BRWD1 did not regulate expression of transcription factors required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations had B cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1-/- mice. These data indicate that in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B cell development.
2018-08-11 | GSE103057 | GEO
Project description:Background: Despite successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises questions about the appropriateness of the Ts65Dn mouse as the “gold standard” for DS research. Here we used the novel Ts66Yah mouse that carries both an extra chromosome and the identical segmental Mmu16 trisomy as Ts65Dn without the Mmu17 non-orthologous region. Methods: Forebrains from embryonic day 18.5 Ts66Yah and Ts65Dn mice, along with euploid littermate controls, were used for gene expression and pathway analyses. Behavioral experiments were performed in neonatal and adult mice. Since male Ts66Yah mice are fertile, parent of origin transmission of the extra chromosome was studied. Results: We mapped 45 protein coding genes to the Ts65Dn Mmu17 non-orthologous, among which 71-82 % are expressed during forebrain development. Several of these genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. Delays in motor development, communication and olfactory spatial memory were present in Ts66Yah but more pronounced in Ts65Dn neonates. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. These deficits were milder when compared to Ts65Dn mice. Conclusions: Our findings suggest that triplication of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may explain why preclinical trials that used this model have unsuccessfully translated to human therapies.
2023-01-16 | GSE222355 | GEO
Project description:The Brwd1 mutation, though having dramatic effects on the spermatocyte transcriptome, had little effect on the oocyte transcriptome. Postmeiotic gene expression is essential for development and maturation of sperm and eggs. In B6/C3H females, Brwd1 ablation causes severe chromosome condensation and structural defects associated with abnormal telomere structure. In contrast to males, transcriptome analysis at the germinal vesicle stage revealed only minor changes in gene expression including a >2 fold overexpression of the histone methyltransferase MLL5 and LINE-1 elements transposons. Thus, loss of BRWD1 function interferes with the completion of oogenesis and spermatogenesis through sexually dimorphic mechanisms. Our results demonstrate that BRWD1 is essential for the epigenetic control of chromosome stability during female meiosis while playing a critical role in haploid gene transcription during the post-meiotic differentiation events of spermiogenesis.
2014-12-31 | GSE56724 | GEO
Project description:B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre–BCR-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5? to each J? recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings represent a paradigm in which,at any particular antigen-receptor locus, specialized mechanisms enforce lineage- and stage-specific recombination. ChIP-seq for 1 transcription factor and 2 histone modifications in flow purified mouse small pre-B cells. ATAC-seq and RNA-seq in WT and Brwd-Mut mouse flow purified small pre-B cells.
2015-08-24 | E-GEOD-63302 | biostudies-arrayexpress
Project description:This project aims to identify transcriptomic changes in the Down Syndrome mouse model (Ts65Dn) in two brain regions, hippocampus and preoptic area. Also, we aim to identify possible transcriptomics rescue effect in Ts55Dn with viral-mediated overexpression of miR200. In total, we have 3 groups of hippocampal and 3 groups of preotic area tissue (WT control virus, 65Dn control virus and 65Dn miR200 - N=4 per group).
2023-05-23 | GSE199974 | GEO
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:Epigenetic Rescue of Autism-like Social Deficits in Shank3-Deficient Mouse Models
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