NUCLEAR MATRIX MEDIATED TRANSCRIPTIONAL CONTROL OF OSTEOBLAST GENE EXPRESSION

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We will address the hypothesis that the nuclear matrix contributes to transcriptional control of cell growth and bone-specific gene expression during progressive development of the osteoblast phenotype and that the nuclear matrix is regulated developmentally in bone cells. Our experimental strategy is initially to characterize the nuclear matrix proteins that exhibit sequence-specific interactions with promoter regulatory sequences of: 1) the cell cycle regulated histone genes expressed only in proliferating osteoblasts; and 2) the osteocalcin gene expressed post-proliferatively in mature osteoblasts undergoing extracellular matrix mineralization. The regulated expression of these nuclear matrix proteins will then be examined in relation to osteoblast differentiation and potential molecular mechanisms associated with nuclear matrix-mediated developmental transcriptional control. We will investigate the developmental responsiveness of the nuclear matrix to TGFBeta, 1,25(OH)2D3 and dexamethasone. Our "working model" is that the nuclear matrix supports osteoblasts proliferation and differentiation by facilitating gene localization as well as the concentration and localization of transactivation factors. These features of nuclear architecture, together with structural properties of the genome, based on chromatin structure and nucleosome organization can influence transcriptional control of genes associated with cell growth and with the post-proliferative, mature differentiating osteoblast. In intact osteoblasts may support the integration of regulatory activities at multiple, independent cis-acting elements, thereby contributing to positive and negative control of transcription by a broad spectrum of physiological mediators that are developmentally and steroid hormone responsive. Experimentally addressing this hypothesis is consistent with the central theme of the Program Project, the involvement of cell structure as its regulates and is regulated by progressive development expression of cell growth and bone cell-related genes.