TY - JOUR
T1 - DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways
AU - Nardone, S.
AU - Sharan Sams, D.
AU - Reuveni, E.
AU - Getselter, D.
AU - Oron, O.
AU - Karpuj, M.
AU - Elliott, E.
N1 - We thank Dr Nili Avidan from the Genomics Core Facility of The Rappaport Family Institute for Research in the Medical Sciences (Haifa, IL, USA) for the preliminary analysis of the Illumina 450K methylation array. In addition, we thank Professor Itzhak Haviv from the Bar Ilan University Faculty of Medicine (Safed, IL, USA) for his informative discussion which improved the quality of this work. We thank the Autism Tissue Program, the Harvard Brain Tissue Resource Center and Oxford University for the control and autism tissues used in this project. This research was supported by the ISRAEL SCIENCE FOUNDATION (grant No. 1047/12) and the National Institute of Psychobiology in Israel.
PY - 2014/9/2
Y1 - 2014/9/2
N2 - Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions characterized by dysfunction in social interaction, communication and stereotypic behavior. Genetic and environmental factors have been implicated in the development of ASD, but the molecular mechanisms underlying their interaction are not clear. Epigenetic modifications have been suggested as molecular mechanism that can mediate the interaction between the environment and the genome to produce adaptive or maladaptive behaviors. Here, using the Illumina 450 K methylation array we have determined the existence of many dysregulated CpGs in two cortical regions, Brodmann area 10 (BA10) and Brodmann area 24 (BA24), of individuals who had ASD. In BA10 we found a very significant enrichment for genomic areas responsible for immune functions among the hypomethylated CpGs, whereas genes related to synaptic membrane were enriched among hypermethylated CpGs. By comparing our methylome data with previously published transcriptome data, and by performing real-time PCR on selected genes that were dysregulated in our study, we show that hypomethylated genes are often overexpressed, and that there is an inverse correlation between gene expression and DNA methylation within the individuals. Among these genes there were C1Q, C3, ITGB2 (C3R), TNF-α, IRF8 and SPI1, which have recently been implicated in synaptic pruning and microglial cell specification. Finally, we determined the epigenetic dysregulation of the gene HDAC4, and we confirm that the locus encompassing C11orf21/TSPAN32 has multiple hypomethylated CpGs in the autistic brain, as previously demonstrated. Our data suggest a possible role for epigenetic processes in the etiology of ASD.
AB - Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions characterized by dysfunction in social interaction, communication and stereotypic behavior. Genetic and environmental factors have been implicated in the development of ASD, but the molecular mechanisms underlying their interaction are not clear. Epigenetic modifications have been suggested as molecular mechanism that can mediate the interaction between the environment and the genome to produce adaptive or maladaptive behaviors. Here, using the Illumina 450 K methylation array we have determined the existence of many dysregulated CpGs in two cortical regions, Brodmann area 10 (BA10) and Brodmann area 24 (BA24), of individuals who had ASD. In BA10 we found a very significant enrichment for genomic areas responsible for immune functions among the hypomethylated CpGs, whereas genes related to synaptic membrane were enriched among hypermethylated CpGs. By comparing our methylome data with previously published transcriptome data, and by performing real-time PCR on selected genes that were dysregulated in our study, we show that hypomethylated genes are often overexpressed, and that there is an inverse correlation between gene expression and DNA methylation within the individuals. Among these genes there were C1Q, C3, ITGB2 (C3R), TNF-α, IRF8 and SPI1, which have recently been implicated in synaptic pruning and microglial cell specification. Finally, we determined the epigenetic dysregulation of the gene HDAC4, and we confirm that the locus encompassing C11orf21/TSPAN32 has multiple hypomethylated CpGs in the autistic brain, as previously demonstrated. Our data suggest a possible role for epigenetic processes in the etiology of ASD.
UR - http://www.scopus.com/inward/record.url?scp=84907342884&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/tp.2014.70
DO - https://doi.org/10.1038/tp.2014.70
M3 - مقالة
SN - 2158-3188
VL - 4
JO - Translational Psychiatry
JF - Translational Psychiatry
M1 - e433
ER -
