# A systematic study of the environmental etiology of autism spectrum disorder using high-throughput behavioral screening

> **NIH NIH R00** · UNIVERSITY OF WASHINGTON · 2024 · $98,198

## Abstract

ABSTRACT
This Diversity Supplement proposal aims to support Vanessa Lopez, an incoming Postdoctoral Fellow, in
extending the objectives of the Parent R00 grant. The focus of this supplement is on elucidating the impact of
disrupting the Top2a-PRC2-H3K27me3 pathway on brain’s epigenetic state at a single-cell level. This goal aligns
closely with the Parent R00's objectives and will further the aims of the Parent R00, particularly Specific Aim 2.
The Parent R00 has uncovered a novel toxicological pathway implicating Top2a in sensing environmental
toxicants during vertebrate development and leading to social behavior deficits in zebrafish and mouse.
Additionally, it has highlighted the role of PRC2 and H3K27me3 in this pathway, especially in regulating autism
risk genes. The proposed research aims to delve deeper into this pathway using single-cell multimodal omics
sequencing and computational analysis.
Bulk sequencing methods used in the Parent R00 provided valuable insights but lacked cell-type-specific
information crucial for understanding complex epigenetic regulations of brain function. To overcome this
limitation, the proposed Diversity Supplement will employ cutting-edge single-cell multimodal omics technologies,
including Paired-Tag and Paired-seq, to map the single-cell transcriptome and epigenome of wild-type larval
zebrafish brains as well as in zebrafish brains depleted of Top2a. This will enable the characterization of cell-
type-specific epigenetic changes induced by Top2a inhibition.
Specific Aim 1 will apply Paired-Tag to profile single-cell transcriptome and H3K27me3 in wild-type and Top2a
knockout zebrafish brains to identify cell-type-specific changes. Specific Aim 2 will deploy Paired-seq to assess
single-cell transcriptome and chromatin accessibility to identify cis-regulatory elements (cCREs) regulated by
the Top2a-PRC2-H3K27me3 pathway and discover toxicant-responsive CREs targeting autism risk genes.
Collaboration with a mentoring team consisting of experts in single-cell multimodal omics analysis, environmental
toxicology, and autism research will provide Ms. Lopez with a unique skill set to conduct her research and
advance her career to becoming an independent researcher. Overall, this Diversity Supplement aims to bridge
knowledge gaps in understanding the molecular mechanisms underlying epigenetic toxicity and its implications
for neurodevelopmental disorders like autism.

## Key facts

- **NIH application ID:** 11100676
- **Project number:** 3R00ES031050-04S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Yijie Geng
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $98,198
- **Award type:** 3
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11100676

## Citation

> US National Institutes of Health, RePORTER application 11100676, A systematic study of the environmental etiology of autism spectrum disorder using high-throughput behavioral screening (3R00ES031050-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11100676. Licensed CC0.

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