- 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)
Type
Exploratory Grants (P20)
Project #
2P20GM103457-06A1
Application #
8737528
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
Budget End
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
Seixas, Cecília; Choi, Soo Young; Polgar, Noemi et al. (2016) Arl13b and the exocyst interact synergistically in ciliogenesis. Mol Biol Cell 27:308-20
Zeng, Fang; Li, Zicong; Cai, Gengyuan et al. (2016) Characterization of Growth and Reproduction Performance, Transgene Integration, Expression, and Transmission Patterns in Transgenic Pigs Produced by piggyBac Transposition-Mediated Gene Transfer. Anim Biotechnol 27:245-55
Huang, Sijia; Kou, Lei; Furuya, Hideki et al. (2016) A Nomogram Derived by Combination of Demographic and Biomarker Data Improves the Noninvasive Evaluation of Patients at Risk for Bladder Cancer. Cancer Epidemiol Biomarkers Prev 25:1361-6
Corley, Michael J; Dye, Christian; D'Antoni, Michelle L et al. (2016) Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment. Sci Rep 6:33310
Fong, Keith S K; Hufnagel, Robert B; Khadka, Vedbar S et al. (2016) A mutation in the tuft mouse disrupts TET1 activity and alters the expression of genes that are crucial for neural tube closure. Dis Model Mech 9:585-96
Pang, Alina P S; Sugai, Christopher; Maunakea, Alika K (2016) High-throughput sequencing offers new insights into 5-hydroxymethylcytosine. Biomol Concepts 7:169-78
Ching, Travers; Peplowska, Karolina; Huang, Sijia et al. (2016) Pan-Cancer Analyses Reveal Long Intergenic Non-Coding RNAs Relevant to Tumor Diagnosis, Subtyping and Prognosis. EBioMedicine 7:62-72
Lu, Liangqun; McCurdy, Sara; Huang, Sijia et al. (2016) Time Series miRNA-mRNA integrated analysis reveals critical miRNAs and targets in macrophage polarization. Sci Rep 6:37446
Garmire, Lana X; Gliske, Stephen; Nguyen, Quynh C et al. (2016) THE TRAINING OF NEXT GENERATION DATA SCIENTISTS IN BIOMEDICINE. Pac Symp Biocomput 22:640-645
Poirion, Olivier B; Zhu, Xun; Ching, Travers et al. (2016) Single-Cell Transcriptomics Bioinformatics and Computational Challenges. Front Genet 7:163

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