Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045688-01
Application #
2777889
Study Section
Project Start
Project End
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655

  Publications

Ali, Syed A; Zaidi, Sayyed K; Dobson, Jason R et al. (2010) Transcriptional corepressor TLE1 functions with Runx2 in epigenetic repression of ribosomal RNA genes. Proc Natl Acad Sci U S A 107:4165-9
Stein, G S; Stein, J L; Lian, J B et al. (2004) Nuclear microenvironments: an architectural platform for the convergence and integration of transcriptional regulatory signals. Eur J Histochem 48:65-76
Stein, Gary S; Lian, Jane B; van Wijnen, Andre J et al. (2004) Runx2 control of organization, assembly and activity of the regulatory machinery for skeletal gene expression. Oncogene 23:4315-29
Stein, Gary S; Lian, Jane B; Stein, Janet L et al. (2003) Intranuclear organization of RUNX transcriptional regulatory machinery in biological control of skeletogenesis and cancer. Blood Cells Mol Dis 30:170-6
Stein, Gary S; Lian, Jane B; Stein, Janet L et al. (2003) Intranuclear trafficking of transcription factors: Requirements for vitamin D-mediated biological control of gene expression. J Cell Biochem 88:340-55
Stein, Gary S; Lian, Jane B; Montecino, Martin et al. (2003) Nuclear microenvironments support physiological control of gene expression. Chromosome Res 11:527-36
Lian, Jane B; Stein, Janet L; Stein, Gary S et al. (2003) Runx2/Cbfa1 functions: diverse regulation of gene transcription by chromatin remodeling and co-regulatory protein interactions. Connect Tissue Res 44 Suppl 1:141-8
Stein, Gary S; Lian, Jane B; Stein, Janet L et al. (2003) Temporal and spatial parameters of skeletal gene expression: targeting RUNX factors and their coregulatory proteins to subnuclear domains. Connect Tissue Res 44 Suppl 1:149-53
Drissi, Hicham; Pouliot, Arlyssa; Koolloos, Christian et al. (2002) 1,25-(OH)2-vitamin D3 suppresses the bone-related Runx2/Cbfa1 gene promoter. Exp Cell Res 274:323-33
Zaidi, Sayyed K; Sullivan, Andrew J; van Wijnen, Andre J et al. (2002) Integration of Runx and Smad regulatory signals at transcriptionally active subnuclear sites. Proc Natl Acad Sci U S A 99:8048-53

Showing the most recent 10 out of 30 publications