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STAG2 modulates environmental toxicant exposures and epigenomic heterogeneity

Award Number: R01ES034250
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/20/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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STAG2 modulates environmental toxicant exposures and epigenomic heterogeneity - ABSTRACT Epidemiological evidence suggests that environmental exposures during development may play a role in disease susceptibility later in life, and researchers have hypothesized that epigenetic changes induced by common toxicants such as pesticides, herbicides, endocrine disruptors, and heavy metals may be facilitating this link 1,2. The mechanisms by which these changes are induced and propagated remain challenging to dissect, largely because environmental toxicant induced changes are often 1) subtle when assayed across the bulk cell population, 2) transient in nature and therefore difficult to reproducibly detect, and/or 3) randomly distributed throughout the genome, making reproducibility and measurement of statistical significance challenging. In fact, most studies trying to link toxicant exposures directly to frank cellular transformation, including our own, have been relative failures. In virtually all cases, in order to see overt transformation, exposure studies need to be conducted in cell or animal models that already have baseline genetic or epigenetic changes that facilitate the progression to malignancy. We have exciting preliminary data that demonstrates that Ewing sarcoma cells demonstrate a significantly elevated level of transcriptional and replication stress (RS), and we propose that environmental exposures may not only induce RS and activate the RSR, but also cause epigenetic changes that precondition cells to allow for survival following expression of driver fusion proteins despite elevated levels of RS. This proposal will focus our efforts on understanding the downstream effects of TCDD exposures in mesenchymal stem cells (MSC) when paired with 2,4-D and 2,4,5-T and investigate the role of STAG2 in modulating downstream molecular events associated with environmental toxicant exposures. Our overall hypothesis is that environmental toxicant exposures cooperate with STAG2 loss to increase replication stress, ultimately leading to genomic and epigenomic instability, and creating a permissive epigenome for fusion gene expression. Three Specific Aims are proposed: SPECIFIC AIM 1: To determine whether environmental toxicant exposures increase baseline levels of replication stress in iMSC and cooperate with STAG2 loss to lead to epigenomic remodeling. SPECIFIC AIM 2: To determine whether environmental toxicant exposures cooperate with STAG2 loss to lead increased clonal genetic and epigenetic heterogeneity. SPECIFIC AIM 3: To determine whether environmental toxicant exposure leads to a permissive epigenome for survival of pre-malignant cells following fusion protein expression.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $597,213 )
2026	2026	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Environmental Health	000	5	1/1/2026	NON-COMPETING CONTINUATION	$597,213
														Subtotal = $597,213

Issue Date FY: 2025 ( Subtotal = $597,213 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Environmental Health	000	4	12/11/2024	NON-COMPETING CONTINUATION	$597,213
														Subtotal = $597,213

Issue Date FY: 2024 ( Subtotal = $597,213 )
2024	2024	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Environmental Health	000	3	12/19/2023	NON-COMPETING CONTINUATION	$597,213
														Subtotal = $597,213

Issue Date FY: 2023 ( Subtotal = $615,456 )
2023	2023	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Environmental Health	001	2	12/30/2022	NON-COMPETING CONTINUATION	$597,213
2023	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Environmental Health	000	1	10/24/2022	NEW	$18,243
														Subtotal = $615,456

Issue Date FY: 2022 ( Subtotal = $578,970 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Environmental Health	000	1	3/18/2022	NEW	$578,970
														Subtotal = $578,970

Grand Total All Awards = $2,986,065

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STAG2 modulates environmental toxicant exposures and epigenomic heterogeneity

Award Number: R01ES034250

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/20/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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