Epigenetic mechanisms act at the interface of genetic and environmental risk factors in autism. Project 2 is designed to investigate to focus on the epigenetic mark of DNA niethylation, as environmental toxins have been demonstrated to reduce global DNA methylation levels while methyl-donor nutrients can be protective. This project will make use primarily of human cord blood samples from the MARBLES study in order to test the hypothesis that epigenetic patterns laid down in eariy life that regulate synapse maturation and immune responses will be impaired in autism through interactions between genetic and environmental factors.
The first aim i s designed to perform a genome-wide analysis of DNA methylation and copy number variation and to study the association of differences in genetics and epigenetics with environmental exposures (from Project 1 and Core C) and nutrients.
The second aim will investigate methylation of a specific gene locus, FOXP3, as an epigenetic marker of regulatory T cells and will make use of immunology expertise and existing participant samples from both MARBLES and CHARGE from Project 3.
The third aim will test a multifactorial mechanistic model of transcription-induced epigenetic memory of perinatal gene x environment interactions at two specific loci, F0XP3 and FMR1, through interactions with Projects 3 and 4. Together these studies will increase understanding of the epigenetic interface between genetic and environmental risk factors in autism, leading to improved diagnosis, prevention, and therapies.

Public Health Relevance

How early life exposures can shape the difference between a normal developmental trajectory and one that leads to autism spectrum disorders is the critical question addressed by this proposal. This project uses both genome-wide and gene focused mechanistic approaches on human samples from a prospective epidemiological study in order to improve understanding, prevention, and treatment of autism spectrum disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES011269-12
Application #
8667440
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Dunaway, Keith W; Islam, M Saharul; Coulson, Rochelle L et al. (2016) Cumulative Impact of Polychlorinated Biphenyl and Large Chromosomal Duplications on DNA Methylation, Chromatin, and Expression of Autism Candidate Genes. Cell Rep 17:3035-3048
Martínez-Cerdeño, Verónica; Camacho, Jasmin; Fox, Elizabeth et al. (2016) Prenatal Exposure to Autism-Specific Maternal Autoantibodies Alters Proliferation of Cortical Neural Precursor Cells, Enlarges Brain, and Increases Neuronal Size in Adult Animals. Cereb Cortex 26:374-83
Crawley, Jacqueline N; Heyer, Wolf-Dietrich; LaSalle, Janine M (2016) Autism and Cancer Share Risk Genes, Pathways, and Drug Targets. Trends Genet 32:139-46
Sirish, Padmini; Li, Ning; Timofeyev, Valeriy et al. (2016) Molecular Mechanisms and New Treatment Paradigm for Atrial Fibrillation. Circ Arrhythm Electrophysiol 9:
Keil, Kimberly P; Lein, Pamela J (2016) DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? Environ Epigenet 2:
Aschner, Michael; Ceccatelli, Sandra; Daneshian, Mardas et al. (2016) Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. ALTEX :
Ciernia, Annie Vogel; LaSalle, Janine (2016) The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat Rev Neurosci 17:411-23
Saldarriaga, Wilmar; Lein, Pamela; González Teshima, Laura Yuriko et al. (2016) Phenobarbital use and neurological problems in FMR1 premutation carriers. Neurotoxicology 53:141-7
Matelski, Lauren; Van de Water, Judy (2016) Risk factors in autism: Thinking outside the brain. J Autoimmun 67:1-7
Bal-Price, Anna; Lein, Pamela J; Keil, Kimberly P et al. (2016) Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. Neurotoxicology :

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