Our program, configured as 3 research projects and 2 cores, continues to address the hypothesis that parameters of nuclear structure (chromatin organization and the assembly and activity of nuclear matrix-associated subnuclear sites for transcription) contribute to gene expression that mediates the onset, progression and maintenance of bone cell phenotypic properties required for skeletal development and homeostasis. We are pursuing an integrated, multidisciplinary team approach that combines molecular, cellular, biochemical and in vivo genetic approaches to define mechanisms by which subnuclear organization of nucleic acids and regulatory proteins facilitates integration of physiological signals to support competency for skeletal gene expression and bone development in vivo. Our program has 1) identified, structurally and functionally (in vitro and in vivo) characterized the intranuclear trafficking signal that directs the Runx2 transcription factor to sites within the nucleus where regulatory machinery governing transcription resides; 2) pioneered investigation of functional interrelationships of chromatin structure, nucleosome organization and chromatin remodeling with skeletal gene expression; 3) demonstrated that Runx2 provides a scaffold for assembly of combinatorial components of skeletal gene expression at strategic sites on target gene promoters and in nuclear microenvironments where threshold concentrations of regulatory proteins dynamically configure functional complexes; 4) provided a new dimension to understanding combinatorial mechanisms that mediate skeletal gene expression by facilitating the organization and activity of regulatory networks; and 5) observed the retention of bone phenotype-specific transcription factors at target genes during mitosis and partitioning to progeny cells providing a novel component of epigenetic control for cell fate determination and lineage commitment. We will focus on further defining spatial and temporal organization and assembly of regulatory complexes for skeletal gene expression by identifying target genes dependent on stable complex formation in subnuclear domains and mechanisms supporting retention of competency for skeletal gene expression during mitotic division of osteoprogenitor cells (project 1), the positive and negative regulation of osteoblastogenesis by multimeric complexes with specialized coregulatory factors in nuclear microenvironments (project 2), and the requirements for chromatin remodeling for induction and progression of the osteoblast phenotype in a vitamin D dependent manner (project 3). Relevance: evaluation of nuclear structure-gene expression interrelationships will provide biological validation of regulatory parameters that are obligatory for skeletal development and may be compromised in metabolic bone disease. Our studies will provide insights into components of nuclear organization that can be targeted for innovative therapy.
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