Genetic and epigenetic regulation of Treg cell fitness by autism-related chromatin remodeler CHD8
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1174721 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31038580_1.fastq.gz | Fastqsanger.gz | |||
| SRR31038580_2.fastq.gz | Fastqsanger.gz | |||
| SRR31038581_1.fastq.gz | Fastqsanger.gz | |||
| SRR31038581_2.fastq.gz | Fastqsanger.gz | |||
| SRR31038582_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 32 |
Similar Datasets
Project description:Chromatin remodeler CHD8 defines a subtype of autism. Its role in regulatory T cells (Tregs) that maintain immune tolerance through suppressing CD4+ and CD8+ effector T cells remain unknown. In this study, we found that Treg-specific CHD8 deletion led to early, fatal inflammatory disorders, due to increased CD4+ and CD8+ effector T cells. CHD8 deletion increased Treg plasticity as evidenced by elevated effector T cell cytokine expression in Tregs. CHIP-seq uncovered that CHD8 binding genes were enriched in PI3K-Akt-mTOR signaling and several other pathways. RNA-seq and ATAC-seq revealed that CHD8 deletion upregulated a number of pathways, notably mTORC1 signaling and its mediated glycolysis that have been reported to promote Treg plasticity. Integrating RNA-seq data with ATAC-seq and/or CHIP-seq data indicates that CHD8 regulates gene expression in either chromatin remodeling- and/or CHD8 binding-dependent or -independent manner. Collectively, our findings suggest that CHD8 plays an important role in maintaining Treg fitness via genetic and epigenetic mechanisms.
2024-12-11 | GSE279810 | GEO
Project description:The loss-of-function mutations in the chromatin remodeler CHD8, a high-risk factor in autism spectrum disorder (ASD), lead to severe developmental delay, however, the underlying mechanisms remains elusive. Here, we use transcriptome and genomic occupancy reveal that CHD8 regulates chromatin accessibility and activates neurogenesis-related genes for cortical neurogenesis.
2022-10-17 | GSE148608 | GEO
Project description:Mutations in the gene encoding the chromatin remodeler CHD8 are a highly penetrant risk factor for autism spectrum disorder (ASD). Although cerebellar abnormalities have been involved in ASD pathogenesis, the underlying mechanisms of CHD8 in the regulation of cerebellar function has remained unknown, however. Here we show that the cerebellar granule neurons–specific deletion of Chd8 manifests reduced proliferation and differentiation of granule neuron progenitors, leading to cerebellar hypoplasia and motor coordination defects in mice. CHD8 was found to regulate the expression of neuronal genes and to be required for maturation of cerebellar granule neurons. Furthermore, we found that CHD8 is preferentially bound to promoter regions and is necessary for modulation of local chromatin accessibilities at promoter regions of active gene. Our results thus uncover a critical role for CHD8 in cerebellar development and have important implications for understanding the cerebellar contributions to ASD pathogenesis.
2021-04-16 | GSE146885 | GEO
Project description:Mutations in CHD8, an ATP-dependent chromodomain-helicase-DNA-binding protein 8, are known to cause a set of Autism Spectrum Disorders (ASD). We found that CHD8 is highly expressed in myelinating oligodendrocytes (OL) and their progenitors in the developing central nervous system (CNS). We performed CHD8 chIP-seq analysis in cultured oligodendrocytes.
2018-06-20 | GSE107919 | GEO
Project description:A dual functions of autism-related chromatin remodeler CHD8 in developmental and adult neurogenesis
| PRJNA625199 | ENA
Project description:Whole-exome sequencing studies have implicated chromatin modifiers and transcriptional regulators in autism spectrum disorder (ASD) through the identification of de novo loss of function mutations in affected individuals. Many of these genes are co-expressed in mid-fetal human cortex, suggesting ASD risk genes converge in regulatory networks that are perturbed in ASD during neurodevelopment. To elucidate such networks we mapped promoters and enhancers bound by the chromodomain helicase CHD8, which is strongly enriched in ASD-associated de novo loss of function mutations, using ChIP-seq in mid-fetal human brain, human neural stem cells (hNSCs), and embryonic mouse cortex. We find that CHD8 targets are strongly enriched for ASD risk genes that converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in significant dysregulation of ASD risk genes targeted by CHD8, as well as additional genes important for neurodevelopment, including members of the Wnt/M-NM-2-catenin signaling pathway. Integration of CHD8 binding data with genetic and gene co-expression data in ASD risk models provides support for additional ASD risk genes. Together, our results suggest that loss of CHD8 function contributes to ASD through regulatory perturbation of other ASD risk genes during human cortical development. Two biological replicates for each ChIP with appropriate Input control Four biological replicates for each condition in knockdown experiments (Ctrl construct, Chd8 target C, and Chd8 target G)
2015-01-21 | E-GEOD-57369 | biostudies-arrayexpress
Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. ChIP-Seq for regulatory factors of BRD4, NSD3, CHD8 and histone modification H3K36me2 in MLL-AF9 transformed acute myeloid leukemia cells (RN2)
2015-12-17 | E-GEOD-71183 | biostudies-arrayexpress
Project description:Truncating mutations of CHD8, encoding a chromodomain helicase, and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA-seq) with genome-wide CHD8 binding (ChIP-seq). Suppressing CHD8 to levels comparable with loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8 binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (p = 1.01x10-9) and CHD8-bound genes (p = 4.34x10-3), which align with previously identified co-expression modules during fetal development. We also find an intriguing enrichment of cancer related gene-sets among CHD8-bound genes (p < 1.9x10-11). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis. RNA-seq in NPCs treated with shRNAs targeting CHD8. For controls, NPCs were treated with shRNAs targeting GFP and LacZ. Infection and sequencing was carried out in two separate batches, with one GFP and one LacZ sample in each batch. All samples were sequenced in two technical replicates.
2014-10-07 | E-GEOD-61491 | biostudies-arrayexpress
Project description:The bromodomain and extraterminal (BET) protein BRD4 is a therapeutic target in acute myeloid leukemia (AML). Here, we demonstrate that the AML maintenance function of BRD4 requires its interaction with NSD3, which belongs to a subfamily of H3K36 methyltransferases. Unexpectedly, AML cells were found to only require a short isoform of NSD3 that lacks the methyltransferase domain. We show that NSD3-short is an adaptor protein that sustains leukemia by linking BRD4 to the CHD8 chromatin remodeler, by using a PWWP chromatin reader module, and by employing an acidic transactivation domain. Genetic targeting of NSD3 or CHD8 mimics the phenotypic and transcriptional effects of BRD4 inhibition. Furthermore, BRD4, NSD3, and CHD8 colocalize across the AML genome, and each is released from super-enhancer regions upon chemical inhibition of BET bromodomains. These findings suggest that BET inhibitors exert therapeutic effects in leukemia by evicting BRD4-NSD3-CHD8 complexes from chromatin to suppress transcription. PolyA+ (illumine TruSeq)/not-so-random (NSR) primers selected RNA-Seq for shRNA/sgRNA-expressing MLL-AF9 transformed acute myeloid leukemia cells (RN2).
2015-12-17 | E-GEOD-71185 | biostudies-arrayexpress
Project description:Meiosis is a key step during germ cell differentiation, accompanied by the activation of thousands of genes through germline-specific chromatin reorganization. The chromatin remodeling mechanisms underpinning early meiotic stages remain poorly understood. Here we focus on the function of one of the major autism genes, CHD8, in spermatogenesis, based on the epidemiological association between autism and low fertility rates. Specific ablation of Chd8 in germ cells results in gradual depletion of undifferentiated spermatogonia as well as failure of meiotic double strand formation followed by arrest at meiotic prophase I and cell death. Transcriptional analyses demonstrate that CHD8 is required for extensive activation of spermatogenic genes in spermatogonia, necessary for spermatogonial proliferation and meiosis. CHD8 directly binds to promoters of genes crucial for meiosis, including H3K4me3 histone methyltransferase genes, meiotic cohesin genes, HORMA domain containing genes, synaptonemal complex genes, and DNA damage response genes. Through transcriptionally regulating the interaction of these meiosis-related genes, we argue that CHD8 contributes to meiotic double strand break formation and subsequent meiotic progression. Our study uncovers an essential role of CHD8 for the proliferation of undifferentiated spermatogonia and the successful progression of meiotic prophase I.
2023-12-31 | GSE252121 | GEO