Enhancer activation mechanisms in cranial neural crest osteochondral differentiation.  

This project seeks to build upon a successful R01 grant that has made significant contributions by showing that the KMT2C and KMT2D histone methylases redundantly function in chondrocyte cellular transitions through catalytic independent mechanisms. We now seek to identify molecular mechansisms involving regulation of alternative chromatin complexes and transcription factors.

Cohesin independent co-function of BRD4 and NIPBL in regulating chromatin and transcription factor genome occupancy.
BRD4 functions in cNCCs to regulate RUNX2 binding to genomic enhancers. We established mouse and cell culture models to study NIPBL function in cNCC osteoblast differentiation. This project will characterize RUNX2 function in several steps of cNCC maintenance and osteochondral differentiation. Genomics will identify overlapping molecular functions of NIPBL and BRD4 in regulating RUNX2 processes. As the BRD4/NIPBL functions appear independent of broader cohesin regulation, we will screen for downstream chromatin factors that modify expression of BRD4 and NIPBL osteogenic targets

Therapeutic potential of enhancer histone methylases in treating osteoarthritis. 

We have demonstrated that KMT2C and KMT2D function developmentally to promote chondrocyte hypertrophic differentiation. We hypothesize that in adult animals, these properties will prove protective for osteoarthritis. The experiments in this proposal will utilize a surgical model of osteoarthritis to examine the protective effects afforded by KMT2C and KMT2D mutation.