scholarly journals Genome-wide DNA methylation patterns in Autism Spectrum Disorder and mitochondrial function

2018 ◽  
Author(s):  
Sofia Stathopoulos ◽  
Renaud Gaujoux ◽  
Colleen O’Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Brain Tissue ◽  
Mitochondrial Function ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Protein Ubiquitination ◽  
Genome Wide ◽  
Differentially Methylated Genes ◽  
Methylation Patterns

AbstractAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by phenotypic heterogeneity and overlapping co-morbidities. The genetic architecture of ASD is complex, with 100’s of risk genes cumulatively contributing to the aetiology of ASD. Epigenetic mechanisms, particularly DNA methylation, have been associated with ASD. The vast majority of ASD molecular research has focused on Northern European populations, with a paucity of data from Africa. This study examines genome-wide DNA methylation patterns in a novel cohort of South African children with ASD and matched, unrelated controls. We performed a whole-genome DNA methylation screen using the Illumina 450K Human Methylation Array. We identify differentially methylated loci associated with ASD across 898 genes (p-value ≤ 0.05). Using a pathway analysis framework, we find nine enriched canonical pathways implicating 32 of the significant genes in our ASD cohort. These pathways converge on two crucial biological processes: mitochondrial metabolism and protein ubiquitination, both hallmarks of mitochondrial function. The involvement of mitochondrial function in ASD aetiology is in line with the recently reported transcriptomic dysregulation associated with the disorder. The differentially methylated genes in our cohort overlap with the gene co-expression modules identified in brain tissue from five major neurological disorders, including ASD. We find significant enrichment of three gene modules, two of which are classified as Mitochondrial and were significantly downregulated in ASD brains. Furthermore, we find significant overlap between differentially methylated and differentially expressed genes from our dataset with a RNA seq dataset from ASD brain tissue. This overlap is particularly significant across the Occipital brain region (padj= 0.0002) which has known association to ASD. Our differential methylation data recapitulate the expression differences of genes and co-expression module functions observed in ASD brain tissue which is consistent with a central role for DNA-methylation leading to mitochondrial dysfunction in the aetiology of ASD.

scholarly journals MOSAIC EPIGENETIC DYSREGULATION OF ECTODERMAL CELLS IN AUTISM SPECTRUM DISORDER

2014 ◽  
Author(s):  
Esther R. Berko ◽  
Masako Suzuki ◽  
Faygel Beren ◽  
Christophe Lemetre ◽  
Christine M. Alaimo ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Dna Mutations ◽  
Genome Wide ◽  
Methylation Assay ◽  
Increased Risk ◽  
Methylation Patterns ◽  
Encoding Protein

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested an homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

scholarly journals DNA Methylation and Susceptibility to Autism Spectrum Disorder

2019 ◽  
Vol 70 (1) ◽  
pp. 151-166 ◽  
Author(s):  
Martine W. Tremblay ◽  
Yong-hui Jiang
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Causative Factor ◽  
Autism Spectrum ◽  
Postnatal Period ◽  
Spectrum Disorder ◽  
Regulation Of Transcription ◽  
Peak Time ◽  
Genome Wide ◽  
Technical Advances

The prevalence of autism spectrum disorder (ASD) has been increasing steadily over the last 20 years; however, the molecular basis for the majority of ASD cases remains unknown. Recent advances in next-generation sequencing and detection of DNA modifications have made methylation-dependent regulation of transcription an attractive hypothesis for being a causative factor in ASD etiology. Evidence for abnormal DNA methylation in ASD can be seen on multiple levels, from genetic mutations in epigenetic machinery to loci-specific and genome-wide changes in DNA methylation. Epimutations in DNA methylation can be acquired throughout life, as global DNA methylation reprogramming is dynamic during embryonic development and the early postnatal period that corresponds to the peak time of synaptogenesis. However, technical advances and causative evidence still need to be established before abnormal DNA methylation and ASD can be confidently associated.

scholarly journals Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study

2018 ◽  
Author(s):  
Yihui Zhu ◽  
Charles E. Mordaunt ◽  
Dag H. Yasui ◽  
Ria Marathe ◽  
Rochelle L. Coulson ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Neuronal Development ◽  
Autism Spectrum ◽  
Child Outcome ◽  
Genome Wide ◽  
Genetic And Environmental Factors ◽  
A Prospective Study ◽  
Methylation Patterns ◽  
Genome Wide Significance

AbstractDNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study of high-risk pregnancies. 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typical controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing, and correlated with expression. Methylation at CYP2E1 associated with both ASD diagnosis and cis genotype, while methylation at IRS2 was unaffected by cis genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.

scholarly journals Analysis of Global and Local DNA Methylation Patterns in Blood Samples of Patients With Autism Spectrum Disorder

2021 ◽  
Vol 9 ◽  
Author(s):  
María Victoria García-Ortiz ◽  
María José de la Torre-Aguilar ◽  
Teresa Morales-Ruiz ◽  
Antonio Gómez-Fernández ◽  
Katherine Flores-Rojas ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Control Group ◽  
Healthy Children ◽  
Blood Samples ◽  
Epigenetic Biomarkers ◽  
Increased Risk ◽  
Methylation Patterns

The goal of this investigation was to determine whether there are alterations in DNA methylation patterns in children with autism spectrum disorder (ASD).Material and Methods: Controlled prospective observational case-control study. Within the ASD group, children were sub-classified based on the presence (AMR subgroup) or absence (ANMR subgroup) of neurodevelopmental regression during the first 2 years of life. We analyzed the global levels of DNA methylation, reflected in LINE-1, and the local DNA methylation pattern in two candidate genes, Neural Cell Adhesion Molecule (NCAM1) and Nerve Growth Factor (NGF) that, according to our previous studies, might be associated to an increased risk for ASD. For this purpose, we utilized blood samples from pediatric patients with ASD (n = 53) and their corresponding controls (n = 45).Results: We observed a slight decrease in methylation levels of LINE-1 in the ASD group, compared to the control group. One of the CpG in LINE-1 (GenBank accession no.X58075, nucleotide position 329) was the main responsible for such reduction, highly significant in the ASD subgroup of children with AMR (p < 0.05). Furthermore, we detected higher NCAM1 methylation levels in ASD children, compared to healthy children (p < 0.001). The data, moreover, showed higher NGF methylation levels in the AMR subgroup, compared to the control group and the ANMR subgroup. These results are consistent with our prior study, in which lower plasma levels of NCAM1 and higher levels of NGF were found in the ANMR subgroup, compared to the subgroup that comprised neurotypically developing children.Conclusions: We have provided new clues about the epigenetic changes that occur in ASD, and suggest two potential epigenetic biomarkers that would facilitate the diagnosis of the disorder. We similarly present with evidence of a clear differentiation in DNA methylation between the ASD subgroups, with or without mental regression.

scholarly journals DNA Methylation of PGC-1α Is Associated With Elevated mtDNA Copy Number and Altered Urinary Metabolites in Autism Spectrum Disorder

2021 ◽  
Vol 9 ◽  
Author(s):  
Sophia Bam ◽  
Erin Buchanan ◽  
Caitlyn Mahony ◽  
Colleen O’Ryan
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Autism Spectrum ◽  
Differential Methylation ◽  
Mtdna Copy Number ◽  
Key Genes

Autism spectrum disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including pathways that affect mitochondrial function. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the etiology of ASD. We measured DNA methylation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), as well as five genes involved in regulating mitochondrial homeostasis to examine mitochondrial dysfunction in an ASD cohort of South African children. Using targeted Next Generation bisulfite sequencing, we found differential methylation (p < 0.05) at six key genes converging on mitochondrial biogenesis, fission and fusion in ASD, namely PGC-1α, STOML2, MFN2, FIS1, OPA1, and GABPA. PGC-1α, the transcriptional regulator of biogenesis, was significantly hypermethylated at eight CpG sites in the gene promoter, one of which contained a putative binding site for CAMP response binding element 1 (CREB1) (p = 1 × 10–6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1α promoter and there was a positive correlation between methylation at PGC-1α CpG#1 and mtDNA copy number (Spearman’s r = 0.2, n = 49, p = 0.04) in ASD. Furthermore, DNA methylation at PGC-1α CpG#1 and mtDNA copy number correlated significantly (p < 0.05) with levels of urinary organic acids associated with mitochondrial dysfunction, oxidative stress, and neuroendocrinology. Our data show differential methylation in ASD at six key genes converging on PGC-1α-dependent regulation of mitochondrial biogenesis and function. We demonstrate that methylation at the PGC-1α promoter is associated with elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored role for DNA methylation in regulating specific pathways involved in mitochondrial biogenesis, fission and fusion contributing to mitochondrial dysfunction in ASD.

scholarly journals LINE-1 and Alu methylation Signatures in Autism Spectrum Disorder and Their Function in The Regulation of Autism-Related Genes

2021 ◽  
Author(s):  
Thanit Saeliw ◽  
Tiravut Permpoon ◽  
Nutta Iadsee ◽  
Tewin Tencomnao ◽  
Tewarit Sarachana ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Dna Methylation ◽  
Autism Spectrum ◽  
Small Sample ◽  
Spectrum Disorder ◽  
Post Mortem ◽  
Global Methylation ◽  
Post Mortem Brain ◽  
Dna Methylation Profiling ◽  
Methylation Profiling

Abstract BackgroundLong interspersed nucleotide element-1 (LINE-1) and Alu elements are retrotransposons whose abilities cause abnormal gene expression and genomic instability. Several studies have focused on DNA methylation profiling of gene regions, but the locus-specific methylation of LINE-1 and Alu elements has not been identified in autism spectrum disorder (ASD).MethodsHere, DNA methylation age was predicted using Horvath’s method. We interrogated locus- and family-specific methylation profiles of LINE-1 and Alu elements (22,352 loci) in ASD blood using publicly-available Illumina Infinium 450K methylation datasets from heterogeneous ASD (n = 52), ASD with 16p11.2 del (n = 7), and ASD with Chromodomain Helicase DNA-binding 8 (CHD8) variants (n = 15). The differentially methylated positions of LINE-1 and Alu elements corresponding to genes were combined with transcriptome data from multiple ASD studies. ROC curve was conducted to examine the specificity of target loci.ResultsEpigenetic age acceleration was significantly decelerated in ASD children over the age of 11 years. DNA methylation profiling revealed LINE-1 and Alu methylation signatures in each ASD risk loci by which global methylation were notably hypomethylated exclusively in ASD with CHD8 variants. When LINE-1 and Alu elements were clustered into subfamilies, we found methylation changes in a family-specific manner in L1P, L1H, HAL, AluJ, and AluS families in the heterogeneous ASD and ASD with CHD8 variants. Our results showed that LINE-1 and Alu methylation within target genes is inversely related to the expression level in each ASD variant. Moreover, LINE-1 and Alu methylation signatures can be used to predict ASD individuals from non-ASD.LimitationsIntegration of methylome and transcriptome datasets was performed from different ASD cohorts. The small sample size of the validation cohort used post-mortem brain tissues and necessitates future validation in a larger cohort.ConclusionsThe DNA methylation signatures of the LINE-1 and Alu elements in ASD, as well as their functional impact on ASD-related genes, have been studied. These findings are considered for further research into DNA methylation profiles and the expression of the LINE-1 and Alu elements in post-mortem brain tissue, which has been linked to ASD pathogenesis.

scholarly journals Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder

2016 ◽  
Vol 19 (11) ◽  
pp. 1454-1462 ◽  
Author(s):  
Arjun Krishnan ◽  
Ran Zhang ◽  
Victoria Yao ◽  
Chandra L Theesfeld ◽  
Aaron K Wong ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Genetic Basis ◽  
Functional Characterization ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Genome Wide

scholarly journals Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hidekazu Kato ◽  
Itaru Kushima ◽  
Daisuke Mori ◽  
Akira Yoshimi ◽  
Branko Aleksic ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Histone Methylation ◽  
Genetic Variants ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Gene Encoding ◽  
Rare Genetic Variants ◽  
Lysine Demethylase ◽  
Methylation Patterns ◽  
Sample Set

AbstractDysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

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