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Understanding gene/environment interactions through epigenomics
Objectives: This study was designed to experimentally determine if PCB-95 and/or BDE-47 play a causal or compounding role in DNA methylation differences observed in human Dup15q neurons using epigenomic approaches.
Methods: Human post-mortem brain tissue samples obtained through the Autism Tissue Program were analyzed for PCB levels using mass spectrometry. Tissue was obtained from individuals with autism, IDIC15, or non-affected controls. In addition, Human SH-SY5Y neuroblastoma cells with an additional maternal chromosome 15 were exposed to PCB in vitro to PCB and methylation regions assessed with whole genome bisulfite sequencing.
Results: Human SH-SY5Y neuroblastoma cells containing an additional maternal chromosome 15 (SH-15M)(Meguro-Horike et al., 2011) were used as a cell culture model of Dup15q and PCB-95 interactions. SH-15M cells model the 15q11-13 gene expression and hypomethylation characteristics of Dup15q brain samples that do not act according to copy number, including lower than expected levels of paternally expressed SNRPN and biallelic GABRB3. Whole genome bisulfite sequencing (MethylC-seq) revealed that SH-15M cells exhibited large genomic domains of partial methylation (PMDs)(Schroeder et al., 2013; Schroeder et al., 2011) that were gained in SH-15M compared to parental SH-SY5Y cells and compounded by PCB-95 exposure. There was an enrichment of genes on 15q11-13 affected by PCB-95 exposure in SH-15M cells, but additional genes on other chromosomes were also found to be within differential PMDs in SH-15M with and without PCB interactions, including other autism candidate genetic loci.
Conclusions: The combination of a large chromosomal duplication (Dup15q) and exposure to a historical persistent organic pollutant (PCB-95) resulted in complex interactions, detected as large-scale genomic changes to neuronal DNA methylation levels. The potential for “two-way street” interactions between genetic and environmental factors across generations should be considered in future ASD studies.
Funded by National Institute of Environmental Health Science 1R01ES021707 and 2P01ES011269, and Department of Defense 1210491.
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