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Single-Molecule Dissection of Hypomethylation-Driven Genome Instability

Award Number: F32GM167172
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/23/2027
PERIOD OF PERFORMANCE END DATE: 01/22/2028

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Single-Molecule Dissection of Hypomethylation-Driven Genome Instability - PROJECT SUMMARY Global DNA hypomethylation is one of the earliest and most pervasive epigenetic alterations in human cancer. It is closely associated with chromosomal instability. On the other hand, DNA hypomethylating agents are approved for leukemia and are being tested across other cancer types. However, it remains unclear whether hypomethylation at specific genomic loci directly increases DNA break susceptibility and how cancer cells repair these lesions. This gap in knowledge limits our ability to safely and effectively use hypomethylating agents. Our preliminary data identify the histone deubiquitinase USP48 as a critical protector of genome integrity under hypomethylating stress, where it is recruited to newly demethylated CpG islands and regulates ubiquitination of non-canonical histones such as macroH2A1. However, the genomic localization of hypomethylation-induced DNA breaks and the molecular mechanism of USP48-dependent repair remain undefined. This F32 proposal will address these gaps by combining innovative technology development with mechanistic chromatin biology. Aim 1 will develop an Oxford Nanopore Technologies (ONT)– based single-molecule platform to jointly map endogenous DNA breaks and DNA methylation and overcome major limitations of existing break-mapping assays. Aim 2 will use our new method as well as established methods, including INDUCE-seq and whole-genome bisulfite sequencing, to define how DNMT1-inhibitor–induced DNA breaks relate to local methylation loss in USP48- deficient leukemia cells. Aim 3 will dissect how USP48 regulates macroH2A1 ubiquitination to promote DNA repair under hypomethylating stress, using CRISPR-engineered mutants, quantitative imaging, and DNA damage–response assays. Together, these studies will establish a mechanistic framework for how global hypomethylation drives genome fragility and identify USP48 and macroH2A1 as key regulators of chromatin stability during DNMT1 inhibition. The proposed work will advance understanding of how hypomethylating drugs cause DNA damage, provide transformative tools for the epigenetics and DNA repair communities, and inform strategies to improve therapeutic efficacy and patient selection. This fellowship will provide the candidate with rigorous training in single-molecule sequencing, DNA damage biology, chromatin biology, and computational analysis, supporting the transition to an independent research career focused on cancer epigenetics and genome stability.


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 = $79,300 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	1	7/23/2026	NEW	$79,300
														Subtotal = $79,300

Grand Total All Awards = $79,300

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Single-Molecule Dissection of Hypomethylation-Driven Genome Instability

Award Number: F32GM167172

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/23/2027

PERIOD OF PERFORMANCE END DATE: 01/22/2028

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