title: Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes.
abstract: Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.2-q13.3 maternal duplication, we find that significant global DNA hypomethylation is enriched over autism candidate genes and affects gene expression. The cumulative effect of multiple chromosomal duplications and exposure to the pervasive persistent organic pollutant PCB 95 altered methylation of more than 1,000 genes. Hypomethylated genes were enriched for H2A.Z, increased maternal UBE3A in Dup15q corresponded to reduced levels of RING1B, and bivalently modified H2A.Z was altered by PCB 95 and duplication. These results demonstrate the compounding effects of genetic and environmental insults on the neuronal methylome that converge upon dysregulation of chromatin and synaptic genes.
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Dunaway
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: M Saharul
authors.initials: MS
authors.lastname: Islam
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: Rochelle L
authors.initials: RL
authors.lastname: Coulson
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: S Jesse
authors.initials: SJ
authors.lastname: Lopez
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Vogel Ciernia
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Chu
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: Dag H
authors.initials: DH
authors.lastname: Yasui
authors.affiliation: Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA; Veterinary Molecular Biosciences, UC Davis, Davis, CA 95616, USA.
authors.forename: Isaac N
authors.initials: IN
authors.lastname: Pessah
authors.affiliation: Genome Center, UC Davis, Davis, CA 95616, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lott
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Mordaunt
authors.affiliation: Advanced Science Research Center, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8640, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Meguro-Horike
authors.affiliation: Advanced Science Research Center, Kanazawa University, 13-1 Takaramachi, Kanazawa 920-8640, Japan.
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Horike
authors.affiliation: Genome Center, UC Davis, Davis, CA 95616, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Korf
authors.affiliation: Medical Microbiology and Immunology, UC Davis, Davis, CA 95616, USA; Genome Center, UC Davis, Davis, CA 95616, USA; MIND Institute, UC Davis, Davis, CA 95616, USA; Center for Children's Environmental Health, UC Davis, Davis, CA 95616, USA. Electronic address: jmlasalle@ucdavis.edu.
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
mesh_terms: D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000187:drug effects; D058674:Chromosome Duplication / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D015894:Genome, Human; D018392:Genomic Imprinting / Q000235:genetics; D006801:Humans; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D063150:Polycomb Repressive Complex 1 / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D002843:Chromatin; C032904:2,2',3,5',6-pentachlorobiphenyl; D011078:Polychlorinated Biphenyls; C471639:UBE3A protein, human; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DNA methylation; autism; chromatin; copy number variants; epigenetic; gene x environment interaction; persistent organic pollutants