Wednesday, April 2, 2025
4/2/2025
Skeletal Patterning Orchestrated by RUNX2 and RUNX3 - PROJECT SUMMARY/ABSTRACT Cartilage growth plates are the primary drivers of skeletal growth and patterning throughout development. Their highly organized structure and dynamic turnover are tightly regulated by complex molecular networks and involve a multi-step program of differentiation, proliferation and maturation of their resident cells, chondrocytes. Supporting this complexity is evidence that hundreds of chondrodysplasias exist in humans, in which growth plate chondrocytes are impaired one way or another. These conditions and many research studies have demonstrated the importance of various factors, including signaling pathways and transcription factors. However, each study was typically limited to one factor and a few targets, and used different experimental models than others. Many gaps thus remain in our definition of the molecular networks regulating growth plate chondrocytes and distinguishing them from articular chondrocytes. These gaps limit our ability to decode the molecular basis and mechanisms underlying not only chondrodysplasias, but also osteoarthritis, where articular chondrocytes often acquire growth plate chondrocyte features, and thus to find treatments direly needed for many of these conditions. Cutting-edge technologies, such as single-cell profiling of transcriptomes and accessible chromatin regions, and genome-wide occupancy of transcription factors are powerful means to make major research progress. This project focuses on RUNX2 and RUNX3, which have long been known to be required for growth plate chondrocyte maturation, but whose full spectrum of actions and interactions with other factors remains sparsely defined. Findings from previous studies and preliminary data support the hypothesis that RUNX2/RUNX3 control a much larger panel of genes than currently appreciated and that these genes are involved both in the multistep program of growth plate chondrocyte specification and differentiation and in skeletal patterning, and that the two factors do this in concert with many other cell type-specific transcription factors and signaling pathway mediators. To test this hypothesis, Aim 1 will thoroughly define the skeletal phenotypes of mice inactivating both genes before or after growth plate formation at the tissue, cellular and molecular levels through histology-based and single-cell transcriptomic assays. Aim 2 will identify the genes whose expressions are directly or indirectly controlled by RUNX2/RUNX3 through genome occupancy profiling and reporter assays. Aim 3 will start to build an atlas of genomic occupancy and functions of all transcription factors driving articular and growth plate chondrocyte fate and differentiation along with, upstream of, or downstream of RUNX2/RUNX3. Scientifically, this project should propel the field of skeletogenesis regulation forward. Translationally, it could help decipher the molecular basis of still unresolved skeletal dysplasias and identify tools for disease therapies. Professionally, it provides an outstanding platform to increase the scientific and technical skills of the postdoctoral fellow and help him transition into a successful independent investigator in skeletal biology research.
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