Dysregulation of Cortical Neuron DNA Methylation Profile in Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is a complex neuropsychiatric syndrome whose etiology includes genetic and environmental components. Since epigenetic marks are sensitive to environmental insult, they may be involved in the development of ASD. Initial brain studies have suggested a dysregulation of epigenetic marks in ASD. However, due to cellular heterogeneity in the brain, these studies have not determined if there is a true change in the neuronal epigenetic signature. Here, we report a genome-wide methylation study on fluorescence-activated cell sorting-sorted neuronal nuclei from the frontal cortex of 16 male ASD and 15 male control subjects. Using the 450 K BeadArray, we identified 58 differentially methylated regions (DMRs) that included loci associated to GABAergic system genes, particularly ABAT and GABBR1, and brain-specific MicroRNAs. Selected DMRs were validated by targeted Next Generation Bisulfite Sequencing. Weighted gene correlation network analysis detected 3 co-methylation modules which are significantly correlated to ASD that were enriched for genomic regions underlying neuronal, GABAergic, and immune system genes. Finally, we determined an overlap of the 58 ASD-related DMRs with neurodevelopment associated DMRs. This investigation identifies alterations in the DNA methylation pattern in ASD cortical neurons, providing further evidence that epigenetic alterations in disorder-relevant tissues may be involved in the biology of ASD.

Cord blood DNA methylome in newborns later diagnosed with autism spectrum disorder reflects early dysregulation of neurodevelopmental and X-linked genes

“…Gene lists were sourced from the reported hits of each paper [6,12,[21][22][23][24][25][26][27][28][29][30][37][38][39][40][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103].…”

“…Epigenome-wide association studies (EWAS) have identified locus-specific differential methylation and epigenetic signatures associated with ASD. EWAS in post-mortem brain have identified differential methylation of genes involved in synaptic transmission and the immune response, with a particular enrichment for open chromatin regions and genes important for microglia [21][22][23][24]. Similarities in brain epigenetic dysregulation have been found between individuals with idiopathic and syndromic ASDs, including Dup15q and Rett syndrome [23,25,26].…”

Methyl-CpG binding domain 2 (Mbd2) is an Epigenetic Regulator of Autism-Risk Genes and Cognition

“…Both genetic and environmental factors are believed to be involved in the etiology of ASD and other neurodevelopmental disorders. DNA methylation has been proposed as an epigenetic interface which links environmental factors to genomic susceptibility in ASD [64,65] and neurodevelopment [66]. MBD proteins as readers of DNA methylation are therefore potential mediators which translate the altered DNA methylation landscape into gene-expression and ultimately behavioral changes.…”

Integrative network analysis reveals biological pathways associated with Williams syndrome

“…Then, we examined the enrichment of nonpsychiatric disorder‐associated genes in each module. The lists of genes associated with atherosclerosis, diabetes mellitus (DM) type 2, and systemic lupus erythematosus (SLE) were obtained from Nardone, Sams, Zito, Reuveni, and Elliott (). We performed a mouse phenotype enrichment analysis using the following mouse phenotype (MP) ontology terms from the Mouse Genome Informatics (MGI) database (Eppig, Blake, Bult, Kadin, & Richardson, ): abnormal social behavior [MP:0002557], abnormal fear/anxiety behavior [MP:0002065], and abnormal learning/memory [MP:0002063].…”