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Molecular mechanisms of chromatin signaling and epigenetic regulation

Award Number: R35GM152184
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Molecular mechanisms of chromatin signaling and epigenetic regulation - PROJECT SUMMARY DNA methylation and histone post-translational modifications (PTMs) are key epigenetic regulators of chromatin accessibility, interaction, and function. Changes in the composition, abundance, and distribution of DNA methylation and histone PTMs, and associated rearrangements in chromatin structure, are defining features of human cancer and other diseases. While much progress has been made connecting epigenetic regulation to cellular function and disease, it is still not clear how these regulatory functions are accomplished with spatial and temporal precision, how these epigenetic signals translate to functional outcomes in chromatin regulation, and how these changes contribute to disease states. Our long-term goal is to translate basic mechanistic understanding of chromatin regulatory function into new strategies for the treatment of human diseases. Toward this goal, we develop and use cutting edge biochemical, genomic, and proteomic technologies to understand the interconnected molecular activities of chromatin regulatory proteins that “read,” “write,” and “erase” DNA methylation and histone PTMs. Our past work focused on defining molecular mechanisms regulating the epigenetic inheritance of DNA methylation through cell divisions. We revealed complex mechanisms involving multivalent DNA and histone associations and allosteric regulation that influence DNA methyltransferase chromatin targeting and substrate specificity. These studies also contributed to the appreciation that DNA methyltransferases utilize ubiquitin-dependent protein interactions to facilitate their enzymatic activities, but the mechanistic details of how DNA methylation and ubiquitin signaling interface are unclear. Our goals in the next five years are to define regulatory and pathologic mechanisms that connect ubiquitin signaling to the epigenetic inheritance of DNA methylation. Toward accomplishing these goals, we will study roles for protein ubiquitination in big picture questions of: 1) how, when, and where DNA methylation regulators are targeted in the genome to carry out their enzymatic functions; 2) how abnormal 5mC patterns arise in cancer and aging cells; and 3) how these changes contribute to other molecular hallmarks of these disease and disease-associated states. To facilitate these studies, we will also 4) develop a new class of ubiquitinated histone affinity reagents that is generalizable for the enrichment of singly and combinatorially modified histone PTM states. Collectively, our studies will continue to define fundamental mechanisms regulating DNA methylation inheritance, reveal pathologic mechanisms associated with abnormal DNA methylation signaling, and introduce new reagents and methods for this field.


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 = $518,400 )
2026	2026	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Biomedical Research and Research Training	000	3	5/22/2026	NON-COMPETING CONTINUATION	$518,400
														Subtotal = $518,400

Issue Date FY: 2025 ( Subtotal = $518,400 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Biomedical Research and Research Training	001	2	5/2/2025	NON-COMPETING CONTINUATION	$518,400
2025	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Biomedical Research and Research Training	000	1	11/8/2024	NEW	$0
														Subtotal = $518,400

Issue Date FY: 2024 ( Subtotal = $518,400 )
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Biomedical Research and Research Training	000	1	7/19/2024	NEW	$513,000
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Biomedical Research and Research Training	001	1	7/26/2024	NEW	$5,400
														Subtotal = $518,400

Grand Total All Awards = $1,555,200

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Molecular mechanisms of chromatin signaling and epigenetic regulation

Award Number: R35GM152184

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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