Functional DNA methylation signatures for genomic loci that confer an increased risk for autism spectrum disorder: 16p11.2 deletions and CHD8 variants
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PROVIDER: PRJNA454698 | ENA |
REPOSITORIES: ENA
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Project description:Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (>200 ASD-risk genes), no single gene mutation accounts for >1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. To investigate the epigenome in patients with ASD, genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450K array in blood from individuals with ASD of heterogeneous, undefined etiology (n=52) and individuals with 16p11.2 deletions (16p11.2del, n=9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n=7), two of the most common genomic variants conferring increased risk for ASD. DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from both heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n=9) and CHD8 (n=9) variants as pathogenic or benign. Our findings that DNAm alterations in each signature targets unique genes in biological pathways relevant to neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. Our study constitutes a novel approach for ASD molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.
2019-09-01 | GSE113967 | GEO
Project description:BackgroundAutism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (> 200 ASD-risk genes), no single gene variant accounts for > 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology (n = 52), and individuals with 16p11.2 deletions (16p11.2del, n = 9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n = 7).ResultsDNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from each other and from heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n = 9) and CHD8 (n = 13) variants as pathogenic or benign. Our findings that DNAm alterations in each signature target unique genes in relevant biological pathways including neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies.ConclusionsDNAm signatures can provide clinical utility complementary to next-generation sequencing in the interpretation of variants of unknown significance. Our study constitutes a novel approach for ASD risk-associated molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.
| S-EPMC6636171 | biostudies-literature
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:Recurrent Copy Number Variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes. In particular, deletion of 16p11.2 is found in patients with autism, developmental delay, and obesity. Patients with deletions or duplications have a wide range of clinical features, and siblings carrying the same deletion often have diverse symptoms. To study the consequence of 16p11.2 CNVs in a systematic manner, we used chromosome engineering to generate mice harboring deletion of the chromosomal region corresponding to 16p11.2, as well as mice harboring the reciprocal duplication. These 16p11.2 CNV models have dosage-dependent changes in gene expression, viability, brain architecture, and behavior. For each phenotype, the consequence of the deletion is more severe than that of the duplication. Of particular note is that half of the 16p11.2 deletion mice die postnatally; those that survive to adulthood are healthy and fertile, but have alterations in the hypothalamus and exhibit a ‘behavior trap’ phenotype—a specific behavior characteristic of rodents with lateral hypothalamic and nigrostriatal lesions. Our findings indicate that 16p11.2 CNVs cause both brain and behavioral anomalies, providing new insight into human neurodevelopmental disorders.
2011-10-03 | GSE32012 | GEO
Project description:CHD8 is an ATP-dependent chromatin-remodeling factor encoded by the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Although many studies have examined the consequences of CHD8 haploinsufficiency in cells and mice, few have focused on missense mutations, the most common type of CHD8 alteration in ASD patients. We here characterized CHD8 missense mutations in ASD patients according to six prediction scores and experimentally examined the effects of such mutations on the biochemical activities of CHD8, neural differentiation of embryonic stem cells, and mouse behavior. Only mutations with high prediction scores gave rise to ASD-like phenotypes in mice, suggesting that not all CHD8 missense mutations detected in ASD patients are directly responsible for the development of ASD. Furthermore, we found that mutations with high scores cause ASD by mechanisms either dependent on or independent of loss of chromatin-remodeling function. Our results thus provide insight into the molecular underpinnings of ASD pathogenesis caused by missense mutations of CHD8.
2024-02-28 | GSE227579 | GEO
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.
2014-10-07 | GSE61491 | GEO
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.
2014-10-07 | GSE61487 | GEO
Project description:Reciprocal deletion and duplication of 16p11.2 is the most common copy number variation (CNV) associated with Autism Spectrum Disorder (ASD) and other developmental disorders, and has significant effect on brain size. We used cortical organoids derived from ASD cases to investigate neurodevelopmental pathways dysregulated by dosage changes of 16p11.2 CNV. We show that organoids recapitulate patients’ macrocephaly and microcephaly phenotypes. Deletions and duplications have “mirror” effects on cell proliferation, maturation and synapse number, consistent with “mirror” effects on brain development in humans. Neuronal migration was decreased in both, deletion and duplication organoids. Transcriptomic and proteomic profiling revealed synaptic defects and neuronal migration as key drivers of 16p11.2 functional effect. We implicate upregulation of small GTPase RhoA involved in regulation of cytoskeletal dynamics, neuron migration and neurite outgrowth as one of the pathways impacted by the 16p11.2 CNV in ASD. Treatment with the RhoA inhibitor Rhosin rescued neuron migration, but not synaptic defects. This study identifies pathways dysregulated by the 16p11.2 CNV during early neocortical development using cortical organoid models. Grant ID: Simons Foundation, #345469 Grant Title: Translational dysregulation of the RhoA pathway in autism Affiliation: University of California San Diego Name: Lilia M. Iakoucheva; Alysson R. Muotri
2021-07-31 | GSE142174 | GEO
Project description:While the neuronal underpinnings of autism spectrum disorders (ASD) are being unraveled, vascular contributions to ASD remain elusive. Here, we investigated postnatal cerebrovascular development in the 16p11.2df/+ mouse model of 16p11.2 deletion ASD syndrome. We discovered that 16p11.2 hemizygosity leads to male-specific, endothelium-dependent structural and functional neurovascular abnormalities. In 16p11.2df/+ mice, endothelial dysfunction resulted in impaired cerebral angiogenesis at postnatal day (P) 14, and in altered neurovascular coupling and cerebrovascular reactivity at P50. Moreover, we showed defective angiogenesis in primary 16p11.2df/+ mouse brain endothelial cells and in iPSC-derived endothelial cells from human 16p11.2 deletion carriers. Finally, we found that mice with endothelium-specific 16p11.2 deletion (16p11.2DEC) partially recapitulated some behavioral changes seen in 16p11.2 syndrome, specifically hyperactivity and impaired motor learning. By showing that developmental 16p11.2 haploinsufficiency from endothelial cells results in neurovascular and behavioral changes in adults, our results point to a potential role for endothelial impairment in ASD.
2020-04-03 | GSE147790 | GEO
Project description:To investigate the cell types and driver genes perturbed by 16p11.2 deletions using cerebral organoids
2022-05-13 | GSE200851 | GEO