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Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome inResponse to Environmental Arsenic Exposure

Award Number: R01ES031846
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Establishing the influence of pollutants on genome function is essential in defining their impact on human health. Environmental pollutants such as inorganic arsenic (iAs) are responsible for over thirteen million deaths yearly. Importantly, 24% of the diseases caused by environmental exposures might have been avoided by disease prevention, diagnosis and the development of safer metal-based therapeutic agents. In order to understand how these pollutants cause disease, we need to understand how pollutants change gene expression. Proper gene regulation is essential for normal growth, development and etiology of diseases such as cancer. Eukaryotic DNA stored as chromatin plays an integral role in gene regulation. At the one- dimensional (1D) level, chromatin is found as nucleosomes and at the three dimensional level (3D), chromatin is found in loops and topological domains, both of which regulate gene expression by allowing accessibility to the DNA wrapped up as chromatin. Inorganic arsenic is a ubiquitous metal that impacts gene regulation through modulating the epigenome. We recently provided the epigenetic landscape (DNA methylation, histone PTMs and histone variants) mediated by iAs. This landscape though important, makes it difficult to decipher whether the observed effects on gene activity are due to local changes in epigenetic environments, or effects caused by remote changes several kilobases away, such as the activity of enhancer(s). Additionally, the effect of the 3D chromatin structure supersedes that at the 1D chromatin level. This 3D information is mediated by CTCF, known as a ‘master weaver’ of the genome, and any dysregulation of the CTCF binding alters this 3D structure, resulting in gene dysregulation. We recently showed that iAs selectively inhibits CTCF from binding to some of its target sites and instigating oncogenic expression patterns. Interestingly, carcinogenesis is not a linear process but involves a several hybrid in-between stages till final cancer state. We therefore hypothesize that by inhibiting CTCF binding, iAs reorganizes the genome to maintain specific topologically-activated domains at the 3D chromatin structure to drive specific oncogenic potentials. To test this hypothesis, we will map CTCF binding (Aim 1), chromatin 3D (Aim 2) and ChIP-seq of histone marks (Aim 3) as cells undergo iAs- mediated carcinogenesis. The knowledge derived from the proposed studies will allow us to characterize the resulting gene regulatory network mediated by iAs exposure, and allow us to unambiguously anchor iAs exposure to changes in the CTCF interactome in the process of iAs-mediated cancer. Additionally, these studies will allow us to decipher how iAs initiates, establishes and maintains particular chromatin signatures that ultimately drive gene expression in iAs pathogenesis. Such studies are critically needed for the identification of translational targets and the development of therapeutic drugs needed in iAs-disease pathology.


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: 2024 ( Subtotal = $565,039 )
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Environmental Health	000	5	3/1/2024	NON-COMPETING CONTINUATION	$565,039
														Subtotal = $565,039

Issue Date FY: 2023 ( Subtotal = $568,959 )
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Environmental Health	003	4	2/22/2023	NON-COMPETING CONTINUATION	$568,959
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Environmental Health	002	3	12/12/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$349,881
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Environmental Health	000	3	12/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2023	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	001	2	12/12/2022	NON-COMPETING CONTINUATION	-$349,881
														Subtotal = $568,959

Issue Date FY: 2022 ( Subtotal = $592,719 )
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Environmental Health	001	3	4/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$592,719
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Environmental Health	002	3	5/13/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	2	4/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $592,719

Issue Date FY: 2021 ( Subtotal = $491,482 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	2	2/23/2021	NON-COMPETING CONTINUATION	$491,482
														Subtotal = $491,482

Issue Date FY: 2020 ( Subtotal = $497,761 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Environmental Health	000	1	5/5/2020	NEW	$497,761
														Subtotal = $497,761

Grand Total All Awards = $2,715,960

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Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome inResponse to Environmental Arsenic Exposure

Award Number: R01ES031846

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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