Genome-wide DNA methylation analysis in Williams syndrome (WS patients vs Controls)
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ABSTRACT:
PROVIDER: PRJNA490275 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genome-wide DNA methylation profiling of WS patients and controls using peripheral blood samples.
2020-04-25 | GSE119778 | GEO
Project description:Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ~28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of Williams syndrome. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren Syndrome Critical Region deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation, and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.
2016-01-19 | GSE71664 | GEO
Project description:Williams Syndrome (WS) is a rare neurodevelopmental disorder caused by heterozygous deletions in a chromosome 7q11.23 region typically encompassing 26-28 genes. WS patients exhibit a wide spectrum of symptoms, including cardiovascular disease, intellectual disability, visuospatial deficits and hypersociability a behavioral profile that contrasts with autism spectrum disorder (ASD). However, the relationship between neuropsychiatric phenotypes and dysregulated gene networks caused by the 7q11.23 deletion is unknown. We report results from a large-scale integrated transcriptome analysis of peripheral blood in clinically evaluated subjects with WS, ASD and matched controls. We identified significantly differential expressed genes in WS as compared with ASD or controls, even after removing genes spanning the 7q11.23 region. Using weighted gene co-expression network analysis (WGCNA), we found that three co-expression modules were upregulated in WS, and were significantly associated with the intermediate phenotypes such as anxiety and attention problems. Notably, these three co-expression modules were only composed of genes located outside of 7q11.23 critical region. One module was associated with immune systems and B cell proliferation. Its top hub gene, BCL11A, is implicated in ASD and chromatin modification. Another module was enriched with genes associated with astrocytes and oligodendrocytes, and the third module was associated with RNA processing and neurons.MicroRNA (miRNA) profiling revealed differentially expressed miRNAs whose targets were enriched in each co-expression module associated with WS. These results identify genes and potential driver miRNAs, located outside of 7q11.23 critical region, that are novel candidates for mediating the neuropsychiatric phenotypes in WS.
2018-11-06 | GSE89595 | GEO
Project description:Williams Syndrome (WS) is a rare neurodevelopmental disorder caused by heterozygous deletions in a chromosome 7q11.23 region typically encompassing 26-28 genes. WS patients exhibit a wide spectrum of symptoms, including cardiovascular disease, intellectual disability, visuospatial deficits and hypersociability a behavioral profile that contrasts with autism spectrum disorder (ASD). However, the relationship between neuropsychiatric phenotypes and dysregulated gene networks caused by the 7q11.23 deletion is unknown. We report results from a large-scale integrated transcriptome analysis of peripheral blood in clinically evaluated subjects with WS, ASD and matched controls. We identified significantly differential expressed genes in WS as compared with ASD or controls, even after removing genes spanning the 7q11.23 region. Using weighted gene co-expression network analysis (WGCNA), we found that three co-expression modules were upregulated in WS, and were significantly associated with the intermediate phenotypes such as anxiety and attention problems. Notably, these three co-expression modules were only composed of genes located outside of 7q11.23 critical region. One module was associated with immune systems and B cell proliferation. Its top hub gene, BCL11A, is implicated in ASD and chromatin modification. Another module was enriched with genes associated with astrocytes and oligodendrocytes, and the third module was associated with RNA processing and neurons. MicroRNA (miRNA) profiling revealed differentially expressed miRNAs whose targets were enriched in each co-expression module associated with WS. These results identify genes and potential driver miRNAs, located outside of 7q11.23 critical region, that are novel candidates for mediating the neuropsychiatric phenotypes in WS.
2018-11-06 | GSE89594 | GEO
Project description:Williams syndrome (WS) is a neurodevelopmental disorder caused by a heterozygous micro-deletion in the WS critical region (WSCR) and is characterized by hyper-sociability and neurocognitive abnormalities. Nonetheless, whether and to what extent WSCR deletion leads to epigenetic modifications in the brain and induces pathological outcomes remains largely unknown. By examining DNA methylation in frontal cortex, we revealed genome-wide disruption in the methylome of individuals with WS, as compared to typically developed (TD) controls. Surprisingly, differentially methylated sites were predominantly annotated as introns and intergenic loci and were found to be highly enriched around binding sites for transcription factors that regulate neuronal development, plasticity and cognition. Moreover, by utilizing enhancer–promoter interactome data, we confirmed that most of these loci function as active enhancers in the human brain or as target genes of transcriptional networks associated with myelination, oligodendrocyte (OL) differentiation, cognition and social behavior. Cell type–specific methylation analysis revealed aberrant patterns in the methylation of active enhancers in neurons and OLs, and important neuron-glia interactions that might be impaired in individuals with WS. Finally, comparison of methylation profiles from blood samples of individuals with WS and healthy controls, along with other data collected in this study, identified putative targets of endophenotypes associated with WS, which can be used to define brain-risk loci for WS outside the WSCR locus, as well as for other associated pathologies. In conclusion, our study illuminates the brain methylome landscape of individuals with WS and sheds light on how these aberrations might be involved in social behavior and physiological abnormalities. By extension, these results may lead to better diagnostics and more refined therapeutic targets for WS.
2023-01-01 | GSE221249 | GEO
Project description:Williams syndrome (WS), caused by a heterozygous microdeletion in 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (Gtf2i) has been linked to hypersociability in WS, though the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in forebrain excitatory neurons caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased mRNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioural deficits. Frontal cortex from WS patients similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.
2019-03-26 | GSE128840 | GEO
Project description:Williams syndrome (WS), caused by a heterozygous microdeletion in 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (Gtf2i) has been linked to hypersociability in WS, though the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in forebrain excitatory neurons caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased mRNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioural deficits. Frontal cortex from WS patients similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.
2019-03-26 | GSE128839 | GEO
Project description:Williams syndrome (WS), caused by a heterozygous microdeletion in 7q11.23, is a neurodevelopmental disorder characterized by hypersociability and neurocognitive abnormalities. Of the deleted genes, general transcription factor II-i (Gtf2i) has been linked to hypersociability in WS, though the underlying mechanisms are poorly understood. We show that selective deletion of Gtf2i in forebrain excitatory neurons caused neuroanatomical defects, fine motor deficits, increased sociability and anxiety. Unexpectedly, 70% of the genes with significantly decreased mRNA levels in the mutant mouse cortex are involved in myelination, and mutant mice had reduced mature oligodendrocyte cell numbers, reduced myelin thickness and impaired axonal conductivity. Restoring myelination properties with clemastine or increasing axonal conductivity rescued the behavioural deficits. Frontal cortex from WS patients similarly showed reduced myelin thickness, mature oligodendrocyte cell numbers and mRNA levels of myelination-related genes. Our study provides molecular and cellular evidence for myelination deficits in WS linked to neuronal deletion of Gtf2i.
2019-03-26 | GSE128838 | GEO
Project description:We have performed comparative transcriptome profile from lymphoblastoid cell lines from four Williams-Beuren syndrome patients and two patients with partial deletions of the region. The goal was to find deregulated genes specifically in WBS versus atypical deletions, and to determine the biological pathways affected in WBS patients. 6 samples were hybridized twice each: once labeled with Cy5 and once labeled with Cy3 (dye-swap). Each sample was hybridized against a pool of five controls of the same gender.
2010-09-09 | E-GEOD-18188 | biostudies-arrayexpress
Project description:JZL184 treatment restores neurological and cardiac phenotypes of a mouse model of Williams-Beuren syndrome
2022-10-11 | GSE164257 | GEO