التفاصيل البيبلوغرافية
| العنوان: |
T5 - . Dna Methylation Profile Of Cortical Neurons In Autism Spectrum Disorder: Specific Alterations In Gabaergic And Immune Response Related Genes. |
| المؤلفون: |
Elliott, Evan1, Nardone, Stefano1, Sharan Sams, Dev1, Reuveni, Eli1 |
| المصدر: |
European Neuropsychopharmacology. Sep2017 Supplement 3, Vol. 27, pS434-S435. 1p. |
| مصطلحات موضوعية: |
*AUTISM spectrum disorders, *DNA methylation, *DIAGNOSIS, *GENETICS |
| مستخلص: |
Background Autism Spectrum Disorder (ASD) is a neuropsychiatric syndrome with a complex etiology. The potential for non-genetic influence to mediate part of the risk of ASD has prompted several studies to date, all showing evidence for epigenetic alterations in autistic subjects. Establishment of DNA methylation during brain development has been widely accepted as key factor in defining neuron molecular identity. However, one of the most challenging barriers faced in epigenetic studies is the cellular mosaicism in the brain, which can mask the discovery of neuron-specific epigenetic phenotypes. Our study determined the neuron-specific dysregulation of DNA methylation patterns in the brains of individuals diagnosed with ASD. Methods In order to unravel the contribution of neuronal population to the entire epigenetic signature in ASD, we employed two techniques: Fluorescent Activated Cell Sorting (FACS) of neuronal nuclei from human postmortem brains, followed by hybridization on 450K Methylation Array (Illumina), that profiles around 485,000 CpG sites throughout the entire genome. Differentially Methylated Regions were determined using the CHAMP bioinformatics package, which runs the bumphunting algorithm. Weighted Gene Coexpression Network Analysis (WGCNA) was performed to identify networks of CpGs whose methyaltion status correlated with the autism phenotype. Results We identified 12 Differentially Methylated Regions (DMRs) at FDR <0.01. Interestingly, multiple genes were part of the GABAergic system whose involvement has been strongly implicated in ASD. Weighted Gene Co-Expression Network Analysis (WGCNA) pinpointed three co-methylation modules correlated to autism/control status at p value <0.0001. Two of them were inversely correlated to autism/control status and were enriched for synaptic and neuronal genes, while the third module showed a direct correlation and was enriched for immune response processes. Finally, we established the specificity of these 3 modules to ASD assessing their enrichment for GWAS databases related to other psychiatric and non-psychiatric disorders. Discussion This study identifies alterations of DNA methylation in cortical neurons as a possible factor involved in the aetiop athogenesis of ASD. We have identified epigenetic dysregulation in the GABAergic system in cortical neurons of individuals with ASD. Multiple previous studies have determined a dysfunction of GABAergic signaling in the autism brain, and our study suggests that this may have an epigenetic origin. In addition, our study determined a dysregulation of genes involved in the immune response, including complement factors. Considering that many of these same genes have important roles in neuronal development, this suggests an interaction between immune response, epigenetics, and neuronal development. This current study also promotes a more systematic use of cell-specific approaches in psychiatric epigenetics. [ABSTRACT FROM AUTHOR] |
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