Investigating the roles of the H3K4 methyltransferases KMT2C and KMT2D in chondrocyte differentiation and endochondral ossification
Active Project Grant Awarded Last action
- Award ID
- F31DE033916
- Recipient
-
University Of North Carolina At Chapel Hill UEI D3LHU66KBLD5 Part of University Of North Carolina System Office
- Awarding agency
-
National Institute of Dental and Craniofacial Research
National Institutes of Health, Department of Health and Human Services
- Obligated
- $261,948
Award facts
- Assistance listing
- 93.121 Oral Diseases and Disorders Research
- Completion date 99% complete
- Place of performance
- Chapel Hill, NC 27599, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $43,938 | |
| Amendment | $43,938 | |
| Amendment | $0 | |
| Amendment | $43,374 | |
| Amendment | $0 | |
| Amendment | $43,374 | |
| Amendment | $0 | |
| Amendment | $43,374 | |
| Amendment | $0 | |
| Original award | $43,374 |
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Quick answers
Who received award F31DE033916?
F31DE033916 was awarded to University Of North Carolina At Chapel Hill by National Institute of Dental and Craniofacial Research (National Institutes of Health) on January 1, 2025.
How much is award F31DE033916 worth?
$261,948 has been obligated on F31DE033916.
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