The long term goal of this project is to understand how dynamic modifications in the chromatin organization of bone specific genes contribute to activation of transcription in response to physiologic regulatory cues. During the past funding period, using the bone specific osteocalcin gene as a paradigm, we established that remodeling of chromatin structure and nucleosome organization supports developmental induction and steroid hormone enhancement of skeletal related transcription. We have also demonstrated that Runx2 plays a critical role in the assembly of transcriptionally active chromatin at an osteoblast specific promoter. By the combined application of molecular, biochemical, cellular and in vivo genetic approaches, we are addressing the hypothesis that Runx2 mediates developmental and steroid hormone responsive modifications in chromatin organization that are functionally linked to transcriptional control of osteoblast specific genes.
The specific aims are directed to defining mechanisms that interrelate chromatin remodeling and Runx2 in controlling accessibility of skeletal gene promoter sequences to factors (e.g., transcriptional co regulators, histone modifying enzymes, and chromatin remodeling complexes) that determine competency for transcription in stable cell lines and in transgenic mice. Furthermore, we will examine the coupling between subriuclear localization of the osteocalcin gene and Runx2/Cbfal intranuclear foci. Our results will interface with those of Project 1, which is defining mechanisms by which Runx2 is targeted to specific submiclear domains, and Project 2, which is defining activities of Runx2 co regulatory factors at the domains. These studies will provide novel insight into the function of Runx2 in regulating promoter architecture for bone specific transcriptional control.
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