Department of Pathology and Laboratory Medicine
Ph.D., University of Paris XI, France, 2000
Postdoctoral, Penn State University and Stowers Institute, 2001-2007
Research in my laboratory is focused on understanding how chromatin remodeling complexes regulate chromatin structure and gene expression in the budding yeast, Saccharomyces cerevisiae.
Modulation of chromatin structure plays a central role in all the activities of the eukaryotic genome (e.g. gene expression, DNA replication, DNA repair, mitosis and meiosis). Chromatin structures can influence the binding and function of numerous proteins that collaborate in all these different events involving the genome.
We are mainly interested in the role played by two protein complexes that remodel chromatin structure and regulate gene expression with an emphasis on cell-cycle dependent transcription: (i) the SWI/SNF complex, an ATP-dependent chromatin remodeling complex, which was the first chromatin remodeling complex to be identified (ii) the HIR co-repressor complex that I recently characterized as a novel nucleosome assembly factor.
The role of chromatin remodeling complexes, such as the SWI/SNF complex, is known to be broadly required for transcriptional regulation, but their specific roles in cell cycle-dependent transcription remain largely unknown. The recently characterized HIR co-repressor complex, which constitutes a novel nucleosome assembly factor, plays also an important role in the regulation of gene transcription, especially on the cell cycle-dependent histone genes. I also identified a very unique feature of the HIR complex which can block SWI/SNF chromatin remodeling activity in vitro, highlighting a potential important role for gene regulation in vivo.
The goal of my laboratory is to gain a detailed understanding of mechanisms involving the yeast SWI/SNF chromatin remodeling complex and the HIR co-repressor complex in gene expression and particularly in cell-cycle dependent transcriptional regulation. This will provide us with considerable insight into how the chromatin structure is regulated in a cell cycle dependent manner.
Furthermore, this work has wider implications in that the chromatin remodeling factors studied, SWI/SNF and HIR (human homologue HIRA), are important in the control of genes involved in development as shown by the embryonic lethality of the corresponding knock-out in mice. They are likely to play important role during stem cell differentiation and epigenetic regulation. Their involvement in carcinogenesis is well-documented and SWI/SNF complex is commonly referred as a tumor suppressor "complex".
Therefore, these studies are helping us to understand how perturbations in these processes affect gene transcription, cell cycle progression, and genetic instability which are important steps leading to human diseases including cancer.
Ferreira ME, Flaherty K, Prochasson P. The Saccharomyces cerevisiae histone chaperone Rtt106 mediates the cell cycle recruitment of SWI/SNF and RSC to the HIR-dependent histone genes. PLoSOne. 2011 6(6):e21113.
Vishnoi N, Flaherty K, Hancock LC, Ferreira ME, Amin AD, Prochasson P. Separation-of-function mutation in HPC2, a member of the HIR complex in S. cerevisiae, results in derepression of the histone genes but does not confer cryptic TATA phenotypes. Biochim Biophys Acta. 2011 Oct;1809(10):557-66.
Amin AD, Vishnoi N, Prochasson P. A global requirement for the HIR complex in the assembly of chromatin. Biochim Biophys Acta. 2011 Jul 23.
Amit AD, Dimova, DK, Ferreira, ME, Vishnoi, N, Hancock, LC, Osley, MA, Prochasson, P. The mitotic Clb cyclins are required to alleviate HIR-medicated repression of the yeast histone genes at the G1/S transition. Biochim Biophys Acta. 2011 Sep 28.
Awad S, Ryan D, Prochasson P, Owen-Hughes T, Hassan AH. The Snf2 homolog Fun30 acts as a homodimeric ATP-dependent chromatin-remodeling enzyme. J Biol Chem. 2010 Mar 26;285(13):9477-84.
Ferreira ME, Prochasson P, Berndt KD, Workman JL, Wright AP. Activator-binding domains of the SWI/SNF chromatin remodeling complex characterized in vitro are required for its recruitment to promoters in vivo. FEBS J. 2009 May;276(9):2557-65.
Chandy M, Gutiérrez JL, Prochasson P, Workman JL. SWI/SNF displaces SAGA-acetylated nucleosomes. Eukaryot Cell. 2006 Oct;5(10):1738-47.
Hassan AH, Awad S, Prochasson P. The Swi2/Snf2 bromodomain is required for the displacement of SAGA and the octamer transfer of SAGA-acetylated nucleosomes. J Biol Chem. 2006 Jun 30;281(26):18126-34.
Prochasson P, Florens L, Swanson SK, Washburn MP, Workman JL. The HIR corepressor complex binds to nucleosomes generating a distinct protein/DNA complex resistant to remodeling by SWI/SNF. Genes Dev. 2005 Nov 1;19(21):2534-9.
Prochasson P, Neely KE, Hassan AH, Li B, Workman JL. Targeting activity is required for SWI/SNF function in vivo and is accomplished through two partially redundant activator-interaction domains. Mol Cell. 2003 Oct;12(4):983-90.
Hassan AH, Prochasson P, Neely KE, Galasinski SC, Chandy M, Carrozza MJ, Workman JL. Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell. 2002 Nov 1;111(3):369-79.
Philippe Prochasson, Ph.D.