This study is designed to test a novel paradigm that the human genome dynamically interacts with the environment and that epigenetic mechanisms are at the interface of genome- environment interactions. The human genome is marked by structural variations including large copy number variations and differences in repetitive sequences. Environmental toxins such as polychlorinated biphenyls (PCBs) can induce DNA hypomethylation. DNA hypomethylation is a known contributor to genomic instability of CpG-rich Alu repeats in the primate lineage. Chromosome 15q11-13 duplication syndrome (Dup15q), is the most common copy number variation observed in neurodevelopmental disorders, and is responsible for 1-3% of autism cases. This proposal is based on the serendipitous finding that human brain samples with Dup15q syndrome showed significantly higher levels of the persistent organic pollutant PCB-95 than controls or idiopathic autism cases. Furthermore, a genetically susceptible mouse perinatally exposed to the related flame retardant BDE-47 exhibited hypomethylation in brain and reduced sociability compared to controls. This study is designed to experimentally determine if PCB-95 and/or BDE-47 play a causal or compounding role in structural rearrangements of 15q using combined genomic and epigenomic approaches. In addition, this study will directly investigate the effect of combined genomic and environmental insults on the integrity of the methylome and transcriptome in human brain samples.
The first aim seeks to experimentally model chromosome 15 duplication in a novel human cell line system to examine effects of PCB-95 or BDE-47 exposures on genomic stability (DNA-seq) and DNA methylation (MethylC-seq) using next generation sequencing technology. In the second aim, the effect of genetic and epigenetic changes on long-range chromatin loop structure within 15q11-q13 will be examined by chromatin conformation capture sequencing (4C-seq) and correlated to specific transcriptional alterations.
The third aim seeks to directly investigate specific 15q gene targets for epigenetic and transcriptional changes in human brain samples with and without chromosome 15 duplication and high PCB-95 levels. The results of these studies are expected to formally test the hypothesis that DNA methylation levels reduced by specific environmental pollutants may result in genomic rearrangements and alterations in long-range chromatin, leading to transcriptional changes. In addition, epigenetic alterations of autism candidate genes involved in synaptogenesis in human brain samples are expected to be uncovered by this approach. Finally, the results of these studies are expected to be broadly relevant to understanding the relationship between the genome, environmental exposures, and the epigenome in human health and disease.

Public Health Relevance

Autism spectrum disorders occur at a frequency as high as 1 in 110 children, but the etiology of autism and other human neurodevelopmental disorders is poorly understood. Past studies in autism etiology have mostly focused on genetic or environmental contributions independently, and any single known contribution only can explain a small percentage of autism cases. Epigenetic mechanisms act at the interface of genetics and environmental factors. This proposal seeks to investigate the specific epigenetic interface of a chromosome duplication syndrome found in 1-3% of autism cases and persistent organic pollutants that accumulates in brain tissue. Cutting-edge sequencing technologies will be utilized to compare the DNA sequence, DNA methylation, and gene expression profiles in a human cell culture model and human postmortem brain samples with chromosome 15 duplication syndrome. These results are expected to be significant for identifying novel diagnostic markers and development treatment and prevention strategies for autism.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
3R01ES021707-03S1
Application #
8914907
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Tyson, Frederick L
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
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Le, Anh; Shibata, Noreene M; French, Samuel W et al. (2014) Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease. Int J Mol Sci 15:8004-23

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