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Regulation of Hematopoiesis by the EZH2-PRC2 Complex

Award Number: R16GM159134
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: 07/21/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Regulation of Hematopoiesis by the EZH2-PRC2 Complex - Project Abstract EZH2 is the catalytic subunit of the PRC2 (Polycomb repressor complex 2) that mediates the trimethylation of histone H3 lysine 27 (H3K27me3), a critical histone modification associated with gene silencing during cell fate specification and development. Overexpression or activating mutations in EZH2 are associated with various types of human cancers, including blood cancer. But the mechanisms by which the overexpressed or overactivated EZH2 causes various cancers or promotes their progression remains largely unclear. We have recently found that EZH2 is lysine-methylated and such methylation regulates EZH2 protein stability. EZH2 therefore joins to a group of proteins that include DNA (cytosine-5)-methyltransferase 1 (DNMT1), SOX2, and HIF1α which undergo methylation-regulated and ubiquitin-dependent proteolysis. Our group has identified a methyl lysine reader, L3MBTL3, that recognizes the methylated K20 in EZH2 to promote its proteolysis by the CRL4DCAF5 ubiquitin ligase complex. Using the CRISPR-Cas9 gene editing, we have generated a mouse knock-in mutant strain that converts the K20 codon to arginine (K20R) in Ezh2 to produce the Ezh2K20R mutant protein that is resistant to the methylation-dependent proteolysis. We found that the homozygous Ezh2K20R mice produced an expansion of hematopoietic stem/progenitor cell (HSPC) compartments in bone marrow with hepatosplenomegaly. With the Ezh2K20R mutant mice as a model, we hope to test the hypothesis that a gain-of-function mutant of Ezh2 may alter the balance of self-renewal and differentiation of stem cells/progenitor cells, a mechanism potentially linked to an overactivated EZH2 in promoting cancer development. We propose to characterize the Ezh2K20R knock-in mice to determine if the Ezh2K20R mutant protein affects the expansion or differentiation, or both, of the hematopoietic progenitor cells and to identify novel partners for Ezh2 during these processes. Our Specific Aim 1 is to characterize if a specific stage in the erythroid lineage progression is affected by the Ezh2K20R mutation. Our Specific Aim 2 is to investigate if Gfi-1b, a protein that is strongly induced by the Ezh2K20R protein in a hematopoietic organ, is a component of Ezh2-PRC2 complex. Our Specific Aim 3 is to use CRISPR-Cas9-mediated gene editing to generate S21A and K20R/S21A knockin mutations. As our earlier studies showing that S21-phosphorylation and K20-methylation are mutually exclusive, we would predict that S21A mutation being a hypomorphic mutation while the K20R/S21A double mutation being a stronger gain-of-function mutation than K20R alone. Through these studies, we hope to understand how Ezh2 orchestrate a developmental program of self-renewal and differentiation to regulate stem/progenitor cell during hematopoiesis.


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 = $149,582 )
2025	2025	BOARD OF REGENTS OF NEVADA SYSTEM OF HIGHER EDUCATION	4505 S MARYLAND PKWY	LAS VEGAS	NV	89154	CLARK	USA	Biomedical Research and Research Training	000	1	7/21/2025	NEW	$149,582
														Subtotal = $149,582

Grand Total All Awards = $149,582

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Regulation of Hematopoiesis by the EZH2-PRC2 Complex

Award Number: R16GM159134

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: 07/21/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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