Histone gene expression is tightly coupled to DNA replication, providing a viable opportunity to directly investigate regulatory mechanisms that are operative during proliferation of hematopoietic stem cells. The goal of this project is to experimentally address transcriptional regulation of histone genes in hematopoietic progenitor cells as a model to define factors that control cell cycle progression. Results obtained can be used to facilitate expansion of cell populations and competency for engraftment and differentiation. Previous studies of promoter sequences and transcription factors that influence cell cycle regulation of histone gene transcription have shown that Site II, the principal cell cycle regulatory element of the histone gene, interacts with cyclin A, CDC-2, and RB-related proteins, as well as IRF-2. These key regulatory factors control both cell growth (tumor suppression) and cell cycle regulatory phosphorylation events. Thus our working hypothesis is that selective occupancy of the proximal regulatory elements of the cell cycle dependent histone gene promoter is linked to growth control in hematopoietic stem cells and to the downregulation of cell growth that accompanies and potentially serves as a determinant for expression of post-proliferative phenotypic properties. We will focus on modifications of the factors required for cell cycle stage- specific transcription of the histone gene and, equally important, for the downregulation of transcription postproliferatively at the onset of differentiation.
Our specific aims are to; 1) characterize the complement of transcription factors that interact with the principal histone gene promoter regulatory elements under cell cycle and cell growth conditions functionally relevant to hematopoietic progenitor cell activity; 2) assess effects of transcription factors modulation on control of histone gene expression in hematopoietic stem cells; 3) address phosphorylation- mediated signalling mechanisms that control activities of histone gene regulatory factors; and 4) determine the consequential effects of modulating cell cycle dependent transcription factor expression in hematopoietic cells on engraftment in myeloablated mice as well as subsequent growth and differentiation.
| Dooner, Gerri J; Colvin, Gerald A; Dooner, Mark S et al. (2008) Gene expression fluctuations in murine hematopoietic stem cells with cell cycle progression. J Cell Physiol 214:786-95 |
| Colvin, Gerald A; Lambert, Jean-Francois; Dooner, Mark S et al. (2007) Murine allogeneic in vivo stem cell homing(,). J Cell Physiol 211:386-91 |
| Kieusseian, Aurelie; Chagraoui, Jalila; Kerdudo, Cecile et al. (2006) Expression of Pitx2 in stromal cells is required for normal hematopoiesis. Blood 107:492-500 |
| Aliotta, Jason M; Keaney, Patrick; Passero, Michael et al. (2006) Bone marrow production of lung cells: the impact of G-CSF, cardiotoxin, graded doses of irradiation, and subpopulation phenotype. Exp Hematol 34:230-41 |
| Zhang, Hui Z; Degar, Barbara A; Rogoulina, Svetlana et al. (2006) Hematopoiesis following disruption of the Pitx2 homeodomain gene. Exp Hematol 34:167-78 |
| Abedi, Mehrdad; Greer, Deborah A; Foster, Bethany M et al. (2005) Critical variables in the conversion of marrow cells to skeletal muscle. Blood 106:1488-94 |
| Quesenberry, Peter J; Colvin, Gerald; Abedi, Mehrdad (2005) Perspective: fundamental and clinical concepts on stem cell homing and engraftment: a journey to niches and beyond. Exp Hematol 33:9-19 |
| Quesenberry, Peter J; Colvin, Gerald A; Abedi, Mehrdad et al. (2005) The stem cell continuum. Ann N Y Acad Sci 1044:228-35 |
| D'Hondt, Lionel; McAuliffe, Christina; Damon, Jeffrey et al. (2004) Circadian variations of bone marrow engraftability. J Cell Physiol 200:63-70 |
| Colvin, G A; Lambert, J-F; Abedi, M et al. (2004) Murine marrow cellularity and the concept of stem cell competition: geographic and quantitative determinants in stem cell biology. Leukemia 18:575-83 |
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