Chromatin remodeling of the bone-specific osteocalcin (OC) gene accompanies transcriptional activation during late stages of osteoblast differentiation. Defining the molecular, cellular, and physiological mechanisms that regulate osteoblast growth and differentiation, within the context of skeletal development and bone formation in vivo, is the long term goal of the NIH grant """"""""Control of Osteoblast Growth and Differentiation (R0l AR39588),"""""""" that serves as the parent grant for this FIRCA proposal. The studies proposed in this renewal will be done primarily in Chile. During the initial funding period of our collaborative program, we established mechanisms mediating nucleosome positioning and specific protein-DNA interactions on the osteocalcin gene promoter. The studies proposed in this renewal application will reveal molecular mechanisms operating in chromatin remodeling of the OC gene during osteoblast differentiation. We will be focused on establishing the components of the chromatin remodeling complexes that promote the changes in chromatin structure associated with basal and vitamin D-enhanced OC transcriptional activity. We hypothesize that BRG-1 containing complexes are responsible for alterations in OC gene chromatin structure. We will also examine the molecular mechanisms involved in targeting these chromatin-remodeling activities to the OC promoter. We hypothesize that sequence-specific transcription factors such as Cbfa1 play a major role in targeting chromatin-remodeling activities to the OC promoter We also propose that the translational positioning of nucleosomes in the OC promoter result from the activity of these targeted chromatin remodeling complexes. To test these hypotheses we will carry out studies using intact osteoblastic cell cultures as well as cell-free systems.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
2R03TW000990-04
Application #
6402368
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Michels, Kathleen M
Project Start
1998-09-30
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
4
Fiscal Year
2001
Total Cost
$40,320
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Villagra, Alejandro; Cruzat, Fernando; Carvallo, Loreto et al. (2006) Chromatin remodeling and transcriptional activity of the bone-specific osteocalcin gene require CCAAT/enhancer-binding protein beta-dependent recruitment of SWI/SNF activity. J Biol Chem 281:22695-706
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Gutierrez, Soraya; Liu, Jilin; Javed, Amjad et al. (2004) The vitamin D response element in the distal osteocalcin promoter contributes to chromatin organization of the proximal regulatory domain. J Biol Chem 279:43581-8
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