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Role of de novo DNMTs in Toxicant Induced Alterations in DNA Methylation

Award Number: R01ES024915
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: 02/01/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Role of de novo DNMTs in Toxicant Induced Alterations in DNA Methylation - DESCRIPTION (provided by applicant): Developmental exposure to environmental chemicals is a significant public health problem. In the United States alone, one in six children has some form of developmental disability. Many of these cases are attributed to developmental exposure to toxicants. There are also strong indications that some of these exposures increase the risk of adult-onset diseases such as diabetes, hypertension and cardiovascular diseases. Recent studies have implicated epigenetic mechanisms such as DNA methylation in the persistent effects of developmental exposure to toxicants. DNA methylation plays an essential role in development and it involves the chemical modification of DNA by the addition of a methyl group to the cytosine nucleotide by DNA methyltransferase (DNMT) enzymes. DNMT3 group of enzymes are responsible for the establishment of de novo methylation patterns, but it is not known how they target specific DNA sequences for methylation, and how toxicants alter the methylation patterns. In this R01 grant application, the investigators propose to investigate the role of DNMT3s in normal development, as well as in the long-term effects of developmental exposure to toxicants. Using zebrafish, a well-established developmental and toxicological model system, the investigators propose to characterize DNMT3 functions and to determine their role in the response to environmental toxicants. In aim 1, the investigators will test the hypothesis that DNMT3s show DNA target specificity, with each DNMT3 paralog targeting a unique set of genes, thereby establishing DNA methylation patterns. They will determine DNMT3 target specificity in vitro by using an episomal methylation assay and characterizing the sequence specificity of recombinant DNMT3 isoforms, and in vivo using DNMT3- knockout zebrafish. In aim 2, the investigators will test the hypothesis that toxicants alter DNA methylatio patterns, and that these alterations are DNMT3-dependent. They will expose wild-type and DNMT3-knockout zebrafish embryos to environmentally relevant toxicants during sensitive windows of development, and determine the effects on DNA methylation patterns using Reduced Representation Bisulfite Sequencing (RRBS), a genome-wide approach for measuring DNA methylation in CpG rich regions of the genome. In Aim 3, the investigators will test the hypothesis that differentially methylated DNA regions in toxicant-exposed embryos show increased occupancy by DNMT3s. They will expose the zebrafish embryos to a toxicant that induces DNA methylation changes and determine chromatin occupancy using Chromatin immunoprecipitation (ChIP) followed by bisulfite sequencing (ChIP-BS-Seq). Overall, the proposed studies will demonstrate the functions of DNMT3s in establishing DNA methylation patterns during normal development and in mediating toxicant-induced effects.


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: 2023 ( Subtotal = -$536 )
2023	2019	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	5	11/21/2022	NON-COMPETING CONTINUATION	-$536
														Subtotal = -$536

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	5	2/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	5	11/9/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $348,072 )
2019	2019	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	5	11/29/2018	NON-COMPETING CONTINUATION	$348,072
														Subtotal = $348,072

Issue Date FY: 2018 ( Subtotal = $365,019 )
2018	2018	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	4	10/31/2017	NON-COMPETING CONTINUATION	$365,019
														Subtotal = $365,019

Issue Date FY: 2017 ( Subtotal = $361,714 )
2017	2017	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	3	11/1/2016	NON-COMPETING CONTINUATION	$361,714
														Subtotal = $361,714

Issue Date FY: 2016 ( Subtotal = $499,205 )
2016	2016	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	2	11/16/2015	NON-COMPETING CONTINUATION	$499,205
														Subtotal = $499,205

Issue Date FY: 2015 ( Subtotal = $478,997 )
2015	2015	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	1	1/28/2015	NEW	$478,997
														Subtotal = $478,997

Grand Total All Awards = $2,052,471

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Role of de novo DNMTs in Toxicant Induced Alterations in DNA Methylation

Award Number: R01ES024915

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: 02/01/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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