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Transfer: DNA Methylation Canyons in Human Cancers: Methods, Target Genes and Functional Consequences

Award Number: R01CA228140
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Transfer: DNA Methylation Canyons in Human Cancers: Methods, Target Genes and Functional Consequences - PROJECT SUMMARY / ABSTRACT Activation of growth-promoting oncogenes, largely driven by genetic alterations, is a key step during tumorigenesis. Meanwhile, tumors are not only genetically, but also epigenetically, distinct from their tissues of origin. Yet, little is known regarding the extent to which epigenetic mechanisms can activate oncogenes. DNA methylation is the most extensively documented epigenetic modification that can influence cell fate and gene expression. For example, promoter hypermethylation that silences tumor suppressor genes is a key epigenetic event in tumorigenesis. In addition, gene-body hypomethylation is positively correlated with gene expression, although the causal relationship remains to be established. Recently, our group and that of Dr. Bing Ren independently reported broad (e.g. >3.5-kb) under methylated regions (UMRs), termed DNA methylation canyons (Nature Genetics 2014) or valleys (Cell 2013), which in most cases span promoters and gene bodies. Canyons exhibit very low levels of methylation (<10%) in almost all normal cells. Canyon-associated genes (~1,100 in each cell type) are enriched in developmental regulators and homeobox genes, many of which exhibit low or no expression in normal cells. However, despite numerous follow-up studies (i.e., ~540 citations for both papers), the functional role of canyons in gene expression and tumorigenesis remains poorly understood. Nevertheless, our preliminary data indicated that canyons found in normal cells are prone to gene-body, but not promoter, hypermethylation in tumors, with the hypermethylated canyon genes surprisingly enriched in oncogenes. Furthermore, our dCas9-mediated DNA methylation editing experiments revealed an unexpected causal role of gene-body canyon hypermethylation in oncogene activation. Therefore, we hypothesize that we can use cancer DNA methylation data from public domains such as The Cancer Genome Atlas (TCGA) and the International Human Epigenomics Consortium (IHEC), as well as powerful bioinformatics algorithms, to identify genes with cancer-specific hypermethylated canyons in thousands of tumors. We further hypothesize that we can test the functional roles of the hypermethylated canyons in cell and animal models using a dCas9-mediated genome-wide methylation screen. The proposed work is expected to identify hypermethylated canyons that can activate oncogenes and promote tumor growth in vitro and in vivo. Thus, this work can fundamentally transform our understanding about how DNA methylation regulates gene expression and tumorigenesis.


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: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	5	12/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $550,194 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	5	12/16/2022	NON-COMPETING CONTINUATION	$505,280
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	5	3/16/2023	NON-COMPETING CONTINUATION	$44,914
														Subtotal = $550,194

Issue Date FY: 2022 ( Subtotal = $550,194 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	001	4	6/8/2022	NON-COMPETING CONTINUATION	$44,914
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	4	12/23/2021	NON-COMPETING CONTINUATION	$505,280
														Subtotal = $550,194

Issue Date FY: 2021 ( Subtotal = $561,422 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	3	1/15/2021	NON-COMPETING CONTINUATION	$561,422
2021	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	004	2	6/11/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$454,455
2021	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	002	2	5/12/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$453,047
2021	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	5/12/2021	NEW	$453,047
2021	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	003	1	6/11/2021	NEW	-$454,455
														Subtotal = $561,422

Issue Date FY: 2020 ( Subtotal = $574,202 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	003	2	9/4/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$453,047
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	001	2	4/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$574,202
2020	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	1	9/4/2020	NEW	-$453,047
2020	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	4/17/2020	NEW	$0
														Subtotal = $574,202

Issue Date FY: 2019 ( Subtotal = $593,614 )
2019	2019	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	12/4/2018	NEW	$593,614
														Subtotal = $593,614

Grand Total All Awards = $2,829,626

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Transfer: DNA Methylation Canyons in Human Cancers: Methods, Target Genes and Functional Consequences

Award Number: R01CA228140

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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