Our program 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, team approach that combines molecular, cellular, biochemical and in vivo genetic analyses 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) demonstrated remodeling of chromatin and nucleosome organization that is linked to developmental induction and steroid hormone enhanced bone specific transcription; 2) identified bone specific activators and co regulators that integrate activities at skeletal gene promoter elements; 3) demonstrated that the Runx2 (Cbfal/AML3) factor is punctately localized at discrete nuclear matrix associated subnuclear sites; and 4) structurally and functionally characterized a unique intranuclear targeting signal that directs Runx2 to sites of transcription as a requirement for skeletal development to proceed in vivo. We will now examine mechanisms that support our fundamental observations that spatial and temporal organization and assembly of regulatory complexes within the nucleus are necessary for expression of genes that control bone formation. Project 1 will investigate mechanisms that direct bone specific transcription factors and coregulatory proteins to sites within the nucleus where developmental and steroid hormone responsive gene expression occurs. Project 2 will determine mechanisms by which the subnuclear organization of Runx2 with coregulatory proteins is functionally coupled to the integration of regulatory cues that control gene expression in the nucleus of osteoblasts and in the multiple nuclei of osteoclasts. Project 3 will pursue mechanisms that control remodeling of chromatin structure of bone specific genes to render promoter elements competent for physiologically responsive regulatory protein interactions. Evaluation of nuclear structure gene expression interrelationships in vitro and in vivo will provide biological validation of regulatory parameters that are obligatory for skeletal development and may be compromised in metabolic bone disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR048818-03
Application #
6745171
Study Section
Special Emphasis Panel (ZAR1-TAS-D (J1))
Program Officer
Sharrock, William J
Project Start
2002-08-01
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$1,444,752
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Yang, Seungchan; Quaresma, Alexandre J C; Nickerson, Jeffrey A et al. (2015) Subnuclear domain proteins in cancer cells support the functions of RUNX2 in the DNA damage response. J Cell Sci 128:728-40
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Zaidi, Sayyed K; Grandy, Rodrigo A; Lopez-Camacho, Cesar et al. (2014) Bookmarking target genes in mitosis: a shared epigenetic trait of phenotypic transcription factors and oncogenes? Cancer Res 74:420-5
Lopez-Camacho, Cesar; van Wijnen, Andre J; Lian, Jane B et al. (2014) CBF? and the leukemogenic fusion protein CBF?-SMMHC associate with mitotic chromosomes to epigenetically regulate ribosomal genes. J Cell Biochem 115:2155-64
Tai, Phillip W L; Wu, Hai; Gordon, Jonathan A R et al. (2014) Epigenetic landscape during osteoblastogenesis defines a differentiation-dependent Runx2 promoter region. Gene 550:1-9

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