- Project 2 Although controversial, epidemiologic studies have indicated that conception through assisted reproductive technologies (ART), such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), presents a risk for autism spectrum disorders (ASD) and other neurological defects. ART has also been implicated in mediating long-term epigenetic dysregulation, thereby contributing to developmental diseases in humans. To date, genetic variance accounts for fewer than 10% of examined ASD cases, reinforcing the notion that environmental and epigenetic factors underlie ASD incidence. Indeed, culture conditions used in current ART procedures appear to modify epigenetic patterns of normal embryonic development. Additionally, we have identified a potential candidate gene, Shank3, whose genetic and/or epigenetic disruption associates with ASD-like phenotypes in mice. However, the extent to which epigenetic dysregulation directly underlies the ART-associated increased risk for ASD remains undetermined. This is in part due to the lack of a gene-by- environment model relevant to ASD or other neurological disorders. To address this, massively parallel high- throughput sequencing technologies will be employed to examine and characterize the DNA methylomes and gene transcriptomes of brain from IVF-, ICSI-, and naturally-conceived mice (Aim 1). Additionally, comprehensive behavioral assessments will be performed on all mice to link observed epigenetic alterations with social and/or cognitive impairments that characterize ASD (Aim 2). By integrating the genome-wide datasets with behavioral information, candidate ART-associated biomarker genes that are epigenetically dysregulated, including Shank3, will be identified and further investigated during the course of embryonic and brain development (Aim 3). Collectively, addressing these proposed aims will yield a detailed, temporally- defined gene network that underscores the relationship between the pre-implantation environment and the epigenetic mechanisms that play critical roles in neurodevelopment, and help establish a gene-by-environment model of ASD for future investigation to better understand its etiology. Importantly, data from this study will lay the foundation for objectively and rationally altering current ART methodologies to reduce the penetrance of ART-associated ASD and related neurological defects in humans. This work is therefore consistent with the mission of NIH/NIGMS in that it will add to the fundamental knowledge about how the environment of early development may alter normal epigenetic processes that adversely impact long-term health and establishes a novel model that can be applied to inform clinical practices.

Public Health Relevance

- Project 2 This research promises to strengthen our basic understanding of the epigenetic events important to brain development that follow fertilization and examines the controversial link between assisted reproductive technologies and autism. A novel gene-by-environment model will be established as a result of this study, to guide clinical practices modified to reduce the frequency of unintended developmental disorders, particularly autism, in children conceived through the use of assisted reproductive technologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
2P20GM103457-06A1
Application #
8737528
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Hawaii
Department
Type
DUNS #
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Alarcon, Vernadeth B; Marikawa, Yusuke (2018) ROCK and RHO Playlist for Preimplantation Development: Streaming to HIPPO Pathway and Apicobasal Polarity in the First Cell Differentiation. Adv Anat Embryol Cell Biol 229:47-68
Ching, Travers; Garmire, Lana X (2018) Pan-cancer analysis of expressed somatic nucleotide variants in long intergenic non-coding RNA. Pac Symp Biocomput 23:512-523
Lee, Ryan W Y; Corley, Michael J; Pang, Alina et al. (2018) A modified ketogenic gluten-free diet with MCT improves behavior in children with autism spectrum disorder. Physiol Behav 188:205-211
Kim, Iris Q; Marikawa, Yusuke (2018) Embryoid body test with morphological and molecular endpoints implicates potential developmental toxicity of trans-resveratrol. Toxicol Appl Pharmacol 355:211-225
Polgar, Noemi; Fogelgren, Ben (2018) Regulation of Cell Polarity by Exocyst-Mediated Trafficking. Cold Spring Harb Perspect Biol 10:
O'Brien, Lori L; Guo, Qiuyu; Bahrami-Samani, Emad et al. (2018) Transcriptional regulatory control of mammalian nephron progenitors revealed by multi-factor cistromic analysis and genetic studies. PLoS Genet 14:e1007181
Poirion, Olivier; Zhu, Xun; Ching, Travers et al. (2018) Using single nucleotide variations in single-cell RNA-seq to identify subpopulations and genotype-phenotype linkage. Nat Commun 9:4892
Alakwaa, Fadhl M; Chaudhary, Kumardeep; Garmire, Lana X (2018) Deep Learning Accurately Predicts Estrogen Receptor Status in Breast Cancer Metabolomics Data. J Proteome Res 17:337-347
Chaudhary, Kumardeep; Poirion, Olivier B; Lu, Liangqun et al. (2018) Deep Learning-Based Multi-Omics Integration Robustly Predicts Survival in Liver Cancer. Clin Cancer Res 24:1248-1259
Poirion, Olivier B; Chaudhary, Kumardeep; Garmire, Lana X (2018) Deep Learning data integration for better risk stratification models of bladder cancer. AMIA Jt Summits Transl Sci Proc 2017:197-206

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