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Project description:Background: Mutations in the chromatin remodelling protein CHD2 have been strongly associated with multiple neurodevelopmental disorders. However the precise function of CHD2 through neuronal development remains largely uncharacterized. Methods: We have used our protocol for generating cortical interneurons from human embryonic stem cells to study the role of CHD2 in brain development Results: This work found that CHD2 binding is largely associated with open and active chromatin Conclusions: As CHD2 plays distinct roles in several aspects of interneuron development, pathogenic CHD2 mutations have high potential to disrupt one or more of these events, contributing to NDDs.
2022-09-21 | GSE182771 | GEO
Project description:Sequence-based genetic testing identifies causative variants in ~50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
2024-06-13 | GSE269416 | GEO
Project description:Background: Mutations in the chromatin remodeller CHD2 have been strongly associated with multiple neurodevelopmental disorders. However the precise function of CHD2 through neuronal development remains largely uncharacterized. Methods: We have used our protocol for generating cortical interneurons from human embryonic stem cells to study the role of CHD2 in cortical interneuron development, by comparing wild type hMGE and hcINs with a model with CHD2 haploinsufficency Results: This work found that CHD2 controls the expresson of genes with rolls in cell-cell interaction in neuronal precursors and directly influences the exprssion of genes necessary for the production of post-mitotic cortical interneurons Conclusions: As CHD2 plays distinct roles in several aspects of interneuron development, pathogenic CHD2 mutations have high potential to disrupt one or more of these events, contributing to neurodevelopmental disorders
2022-09-21 | GSE182770 | GEO
Project description:Integrative analysis of colorectal cancer (CRC) whole genomes and matched transcriptomes revealed that somatic promoter mutations are associated with increased Chromodomain helicase DNA-binding protein 2 (CHD2) levels. In both primary and metastatic CRC patients, elevated CHD2 levels are associated with worse prognosis and overall survival. We find that CHD2 increases promoter-transcription start site-chromatin accessibility and transcriptional upregulation of multiple oncogenes. In vitro, elevated CHD2 promoted CRC cell proliferation, migration and growth. In orthotopic xenografts, CHD2 promoted higher tumor burden and abdominal metastases, most prominently to the liver. FTD/TPI is an FDA approved chemotherapy for advanced chemo-refractory CRC. In orthotopic CRC models, FTD/TPI was highly effective in reducing metastases and prolonging survival for CHD2 high expressing CRCs. Thus, high CHD2 expression may be a potential CRC chemopredictive biomarker for FTD/TPI. Overall, these results provide new insights into the role of non-coding mutations and CHD2 levels to promote CRC growth and metastasis.
2021-02-12 | GSE146398 | GEO
Project description:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.
2023-03-11 | PXD032277 | Pride
Project description:We demonstrate that chromodomain helicase DNA-binding domain 2 (Chd2) is required to maintain the differentiation potential of mouse ESCs. Chd2-depleted ESCs showed suppressed expression of developmentally regulated genes upon differentiation and subsequent differentiation defects without affecting gene expression in the undifferentiated state. Furthermore, chromatin immunoprecipitation followed by sequencing revealed alterations in a proportion of nucleosomes of developmentally regulated genes in Chd2-depleted ESCs to enhance histone variant H3.3 enrichment, leading to elevated trimethylation of histone H3 lysine 27.Chd2 is essential to prevent suppressive chromatin formation in developmentally regulated genes and determines subsequent effects on developmental processes in the undifferentiated state.
2017-05-15 | GSE96660 | GEO
Project description:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.
2022-11-15 | GSE198581 | GEO
Project description:Considerable evidence suggests loss of function mutations in the chromatin remodeler, CHD2, contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show Chd2+/- mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2+/- mice, including alterations in neurogenesis, synaptic transmission and disease-related genes. Deficits in interneuron density and memory caused by Chd2+/- were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory.
2018-10-18 | GSE112196 | GEO
Project description:Long noncoding RNAs (lncRNAs) are enriched in regions flanking transcription- and chromatin-associated genes, but the functional importance of such co-location events is largely unclear. Chromodomain helicase DNA binding protein 2 (Chd2) is chromatin remodeller with various reported functions in cell differentiation and DNA damage response. Heterozygous mutations in human CHD2 have been implicated in epilepsy, neurodevelopmental delay, and intellectual disability. Here we show that Chaser, a highly conserved long noncoding RNA transcribed from a region in close proximity to the transcription start site of Chd2 and on the same strand, acts in concert with the CHD2 protein to maintain proper Chd2 expression levels. Loss of Chaser in mice leads to substantially increased levels of Chd2 mRNA and protein in the embryo and in adult tissues, early postnatal lethality in homozygous animals, and severe growth retardation in heterozygotes. Mechanistically, over-production of Chd2 induced by loss of Chaser leads to increased transcriptional interference by inhibiting promoters found downstream of highly expressed genes. We further show that Chaser production represses Chd2 expression solely in cis, and the phenotypic consequences of Chaser loss are rescued when Chd2 is perturbed as well. Targeting Chaser is thus a potentially viable strategy for increasing CHD2 levels in haploinsufficient individuals.
2019-09-23 | GSE124375 | GEO
Project description:We demonstrate that chromodomain helicase DNA-binding domain 2 (Chd2) is required to maintain the differentiation potential of mouse ESCs. Chd2-depleted ESCs showed suppressed expression of developmentally regulated genes upon differentiation and subsequent differentiation defects without affecting gene expression in the undifferentiated state. Furthermore, chromatin immunoprecipitation followed by sequencing revealed alterations in a proportion of nucleosomes of developmentally regulated genes in Chd2-depleted ESCs to enhance histone variant H3.3 enrichment, leading to elevated trimethylation of histone H3 lysine 27.Chd2 is essential to prevent suppressive chromatin formation in developmentally regulated genes and determines subsequent effects on developmental processes in the undifferentiated state.
2017-05-15 | GSE96661 | GEO