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Investigating the roles of the H3K4 methyltransferases KMT2C and KMT2D in chondrocyte differentiation and endochondral ossification

Award Number: F31DE033916
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2026

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Investigating the roles of the H3K4 methyltransferases KMT2C and KMT2D in chondrocyte differentiation and endochondral ossification - Project Summary Chromatin-modifying enzymes that are associated with enhancer function are frequently mutated in human craniofacial disorders. Kabuki syndrome (KS) is a craniofacial development disorder characterized by mutations in KMT2D, a histone H3 lysine 4 (H3K4) methyltransferase. Neural crest cells (NCCs) are the stem cells from which anterior facial bone and cartilage originate. Our preliminary studies show that mouse NCC deletion of KMT2D results in a lack of cranial base chondrocyte hypertrophic differentiation. As KS patients present with skeletal defects that may result from abnormal chondrocyte differentiation, understanding the mechanism of KMT2D function in this differentiation process is crucial to a better understanding of both craniofacial and skeletal development disorders. This proposal will assess KMT2D’s molecular mechanism in Aim 1 by interrogation of KMT2C/D-deficient NCCs in culture for changes in KMT2D genome binding, chromatin accessibility, differential gene expression, and localization of histone-methylation at enhancer regions utilizing genomic methodologies during chondrocyte differentiation. As previous publications have indicated methylase-independent roles for KMT2D, this proposal will utilize KMT2D rescue constructs to identify critical domains and non-enzymatic roles of KMT2D in cranial chondrocyte differentiation using genomics and genetic approaches. Aim 2 will explore the cellular mechanism of chondrocyte-specific loss of KMT2C/D on cranial base formation using histology, immunofluorescence, and other imaging approaches. Long bone growth plates will also be examined in chondrocyte-specific KMT2D mutant mice for morphological and molecular changes of chondrogenic differentiation markers to assay broader KMT2D-dependent chondrocyte mechanisms. Collectively, this proposal will ascertain the novel functional roles that KMT2C and KMT2D play in regulating chondrocyte differentiation and the results of this study will implicate epigenetic modifiers in the progression and therapeutics of skeletal disease.


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 = $43,938 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	2	12/4/2025	NON-COMPETING CONTINUATION	$43,938
														Subtotal = $43,938

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	1	2/28/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $43,374 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	000	1	7/18/2024	NEW	$43,374
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Oral Diseases and Disorders Research	001	1	7/18/2024	NEW	$0
														Subtotal = $43,374

Grand Total All Awards = $87,312

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Investigating the roles of the H3K4 methyltransferases KMT2C and KMT2D in chondrocyte differentiation and endochondral ossification

Award Number: F31DE033916

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2026

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