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Persistent transcriptional changes induced by nickel through epigenetic alterations

Award Number: R01ES031402
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: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Persistent transcriptional changes induced by nickel through epigenetic alterations - Project Summary Nickel (Ni) compounds are environmental toxicants, prevalent in the atmosphere due to their use in several industrial processes, as well as extensive consumption of Ni containing products such as stainless steel, batteries, medical devices and medical implants. In addition, combustion of fossil fuels is a major source of Ni contamination in the atmosphere. Exposure to Ni is a major human health hazard, associated with a multitude of health risks including allergic contact dermatitis, bronchitis, pulmonary fibrosis, and pulmonary edema. Moreover, epidemiological studies indicate cancer development as a major outcome of Ni exposure. However, the molecular basis of Ni-induced diseases remains poorly understood. To better understand the molecular mechanisms underlying Ni-induced diseases, we investigated the effects of Ni-exposure on human epithelial cells. Our studies show that Ni-exposure-induced gene expression changes persist long after the cessation of exposure. This resulted in the cells undergoing epithelial-mesenchymal transition (EMT), and the EMT phenotype continued long after the termination of exposure. EMT is the process in which polarized epithelial cells lose cell-cell adhesion and acquire invasive and migratory mesenchymal properties. EMT is implicated in a number of diseases associated with Ni-exposure including asthma, fibrosis, cancer and metastasis. Therefore, our results suggest that persistent transcriptional changes caused by Ni exposure are likely important in the etiology of Ni-exposure associated diseases. The overarching goal of this grant is to understand the mechanisms that drive long-term transcriptional changes caused by Ni exposure. Our preliminary results suggest that Ni-exposure disrupts chromatin regulation mediated by the histone modification, H3K27me3 and the zinc finger protein, CTCF. Based on our preliminary results, we hypothesize that Ni-exposure increases chromatin accessibility through H3K27me3 loss, causing gene upregulation. CTCF binds the newly accessible chromatin and prevents H3K27me3 re-establishment after termination of Ni-exposure, thereby persistently altering gene expression. In Aim 1, we will investigate the role of H3K27me3-loss in Ni- induced persistent gene expression alterations in human lung epithelial cells. In Aim 2, we will investigate the mechanisms underlying Ni-induced persistent chromatin alterations by knocking-down CTCF and by disrupting CTCF binding sites using CRISPR/Cas9 system to examine if loss of CTCF binding could reverse Ni-induced persistent transcriptional changes. In Aim 3, we will examine the functional outcome of Ni-induced persistent transcriptional changes by investigating the tumor generating potential of Ni-exposed cells in in mice. The overall impact of our study will be the identification of the mechanisms underlying long-term transcriptional changes caused by nickel exposure, which will reveal the molecular basis of its pathogenicity, and will have major human health implications.


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 = $0 )
2026	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	5	2/23/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $401,167 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	5	10/23/2023	NON-COMPETING CONTINUATION	$401,167
														Subtotal = $401,167

Issue Date FY: 2023 ( Subtotal = $413,876 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	4	11/1/2022	NON-COMPETING CONTINUATION	$413,876
														Subtotal = $413,876

Issue Date FY: 2022 ( Subtotal = $421,631 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	3	10/27/2021	NON-COMPETING CONTINUATION	$421,631
														Subtotal = $421,631

Issue Date FY: 2021 ( Subtotal = $422,102 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	2	10/30/2020	NON-COMPETING CONTINUATION	$422,102
														Subtotal = $422,102

Issue Date FY: 2020 ( Subtotal = $453,988 )
2020	2020	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Environmental Health	000	1	12/26/2019	NEW	$453,988
														Subtotal = $453,988

Grand Total All Awards = $2,112,764

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Persistent transcriptional changes induced by nickel through epigenetic alterations

Award Number: R01ES031402

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: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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