Wednesday, March 18, 2026 3/18/2026

Molecular basis for aberrant de novo DNA methylation in cancer

Award Number: R01CA266978
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/07/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Molecular basis for aberrant de novo DNA methylation in cancer - PROJECT SUMMARY Methylation of cytosine in the context of CpG dinucleotides is an essential and highly conserved chromatin modification. It plays a critical role in gene regulation, cell differentiation and organismal development. Aberrant patterns of DNA methylation are commonly observed in human diseases including cancer. CpG islands (CGIs), regions with a high frequency of CpG sites found at the promoters of ~40% mammalian genes, are devoid of DNA methylation in normal tissues but become hypermethylated in tumors, leading to the silencing of many tumor suppressor genes. However, the molecular mechanisms underlying CGI hypermethylation in cancer remain poorly understood, and therefore therapeutic strategies that specifically target CGI hypermethylation are lacking. DNA methylation is established by the DNMT3 family of de novo DNA methyltransferases. The DNMT3 family includes two catalytically active members, DNMT3A and DNMT3B. DNMT3A has two splice variants DNMT3A1 and DNMT3A2. While DNMT3A2 and DNMT3B are expressed during early development, DNMT3A1 is the main de novo DNA methyltransferase expressed in differentiated tissues. We and others have previously demonstrated that DNMT3A1 contains regulatory domains interacting with histone post-translational modifications (PTMs) to guide its genomic targeting to regions marked by H3K36 di- and tri-methylation (H3K36me2/3). Our collaborative preliminary studies have identified an additional functional domain unique to DNMT3A1 that facilitates its interaction with histone H2AK119 mono-ubiquitination (H2AK119Ub), a PTM catalyzed by Polycomb Repressive Complex 1 (PRC1). These findings resonate with meta-analyses of patient tumor samples, which revealed a strong correlation between CGIs that gain methylation in cancers and those regulated by Polycomb complexes in normal tissues. We will pursue a hypothesis that the redistribution of DNMT3A1 from H3K36 methylation to H2AK119ub-marked CGIs drives CGI hypermethylation and neoplastic transformation. To test this hypothesis, we will employ a multidisciplinary approach that leverages the complementary expertise of Armache and Lu labs, spanning from chromatin biochemistry, structural study to cancer biology and epigenomics. These studies will reveal the molecular mechanisms of DNMT3A1 regulation by H3K36 methylation and H2AK119Ub and uncover how the balance between these PTMs mediates the recruitment, activity and function of DNMT3A1 in healthy tissues and tumors. Expected results will provide an enhanced understanding of the dynamics, cause and consequence of CGI hypermethylation – a molecular hallmark of human cancers that remains a key focus of the field. Furthermore, they will lay the foundation for developing inhibitors that target the interaction of DNMT3A1 with H2AK119Ub to specifically reverse cancer- associated CGI hypermethylation, which are expected to show less toxicity compared to current FDA-approved unspecific DNA hypomethylating agents.


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 = $479,168 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	000	5	1/27/2026	NON-COMPETING CONTINUATION	$479,168
														Subtotal = $479,168

Issue Date FY: 2025 ( Subtotal = $532,409 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	000	4	1/27/2025	NON-COMPETING CONTINUATION	$479,168
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	001	4	5/22/2025	NON-COMPETING CONTINUATION	$53,241
														Subtotal = $532,409

Issue Date FY: 2024 ( Subtotal = $505,789 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$26,621
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	1/23/2024	NON-COMPETING CONTINUATION	$479,168
														Subtotal = $505,789

Issue Date FY: 2023 ( Subtotal = $521,760 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	000	2	1/31/2023	NON-COMPETING CONTINUATION	$521,760
														Subtotal = $521,760

Issue Date FY: 2022 ( Subtotal = $549,784 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	000	1	2/7/2022	NEW	$549,784
														Subtotal = $549,784

Grand Total All Awards = $2,588,910

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Molecular basis for aberrant de novo DNA methylation in cancer

Award Number: R01CA266978

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/07/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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