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Regulation of DNA methylation inheritance in colon cancer

Award Number: R50CA315355
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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Regulation of DNA methylation inheritance in colon cancer - PROJECT SUMMARY Disruptions in the mechanisms that maintain DNA methylation patterns are a hallmark of cancer and contribute to genome instability and tumor suppressor gene silencing; however, the underlying processes that drive cancer progression and influence response to therapy remain incompletely understood. Since 2015, Dr. Rochelle Tiedemann, the Research Specialist for this R50 application, has led the integrative bioinformatics and genomic analysis efforts in the NCI-funded research program of Unit Director Dr. Scott Rothbart at the Van Andel Institute. This program investigates how ubiquitin signaling regulates DNA methylation inheritance and epigenetic reprogramming in colon cancer (R01CA283463). Dr. Tiedemann’s unique expertise at the intersection of molecular biology and computational epigenomics has been central to defining the mechanistic and therapeutic dimensions of DNMT1 and UHRF1 function in epigenetic inheritance. Dr. Tiedemann’s work has been foundational to discoveries driving Dr. Rothbart’s research program, demonstrating that DNMT1 methyltransferase activity in cells depends on its ability to read ubiquitin and defining how this interaction shapes genome-wide DNA methylation maintenance. Through the development of experimental models and integrative bioinformatic analysis of DNA methylation, chromatin, and transcriptomic datasets, she revealed that disrupting DNMT1’s ubiquitin reader domain produces global hypomethylation patterns resembling catalytic inactivation, uncovering a novel therapeutic vulnerability. Her analyses further established that UHRF1 ubiquitin ligase activity sustains DNA methylation at low-density CpGs, helping to maintain DNA methylation patterns that are frequently lost in cancer. This R50 Research Specialist Award will provide career stability for Dr. Tiedemann to continue leading critical computational and experimental integration efforts across all aims of Dr. Rothbart’s NCI-funded research program: defining ubiquitin signaling networks that regulate DNA methylation inheritance (Aim 1), establishing the oncogenic potential of UHRF1 overexpression in colon cancer (Aim 2), and investigating the role of histone ubiquitin-methylation crosstalk in resistance to DNA hypomethylation therapy (Aim 3). This work incorporates genetically engineered mouse models to determine how disruption of ubiquitin-dependent DNA methylation maintenance influences tumor initiation, progression, and therapeutic response in physiologically relevant in vivo systems. In addition to leading bioinformatic efforts, Dr. Tiedemann will continue to train and mentor junior scientists in data analysis and integrative study design. These studies will reveal fundamental causes and consequences of abnormal DNA methylation signaling in colon cancer and identify new therapeutic strategies to enhance the efficacy of DNA hypomethylation therapy for patients.


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 = $119,105 )
2026	2026	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	1	8/6/2026	NEW	$119,105
														Subtotal = $119,105

Grand Total All Awards = $119,105

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Regulation of DNA methylation inheritance in colon cancer

Award Number: R50CA315355

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/06/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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