Senior Scientist, Regenerative Medicine, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute
Assistant Professor, Department of Cellular and Molecular Medicine, University of Ottawa
Assistant Professor, Department of Medicine, University of Ottawa
Canadian Research Chair in Epigenetic Regulation of Transcription
Training
Research Associate - Fred Hutchinson Cancer Research Center (Seattle, WA, United States)
Post-Doctoral Fellow - Institut de Génétique et de Biologie Moléculaire et Cellulaire (Strasbourg, France)
Ph.D. - Queen’s University (Kingston, ON, Canada)
B.Sc. - Queen’s University (Kingston, ON, Canada)
Research Interest
Regulation of gene expression during mammalian development
Keywords
Chromatin, Transcription, Gene Expression, MyoD, Myogenesis, Development, Epigenetics, Coactivators, Promoters, Muscle, Muscular Dystrophy, Stem Cells
Research Activities
The goal of our research program is to understand the mechanisms by which tissue-specific patterns of gene expression are established during development, and how this can be reproduced in stem cells. While our interests cover all transcriptional regulatory factors, our current research focus is transcriptional activators implicated in myogenesis. This system has become the paradigm for studying gene expression during development due to the fact that exogenous expression of MyoD in a large number of cell lines is sufficient to initiate a temporally ordered and reproducible program of gene regulation leading to muscle differentiation. To understand how MyoD establishes muscle specific gene expression, our group is using a combination of biochemistry, cell biology, molecular biology, genomics, and proteomics.
We have recently demonstrated that the trithorax group protein Ash2L (and its associated methyltransferases) help establish muscle specific gene expression at muscle specific promoters. Ash2L is targeted to muscle specific promoters through the transcriptional activator Mef2d and is recruitment is regulated through the p38 MAPK signaling pathway. While Mef2d is not a muscle specific transcriptional activator, it’s DNA binding elements very often localize adjacent to those of MyoD in the promoters of muscle specific genes.
Our ongoing research is directed towards understanding the role of different transcriptional regulators in generating chromatin environments that establish and maintain tissue specific gene expression patterns.
Figure 1. Model for the integration of p38 MAPK signaling pathway with Mef2 dependent recruitment of the Ash2L complex to muscle specific promoters. Prior to activation of p38, MyoD/E47(MD/E) cooperate with Mef2d dimers (homo- or heterodimers) to establish a transcriptionally poised promoter through recruitment of the acetyltransferase p300 and RNA Polymerase II (Pol II). This leads to acetylation of nucleosomes on histone H4 within the promoter. As differentiation proceeds, cell-cell contact activates the membrane bound receptor Cdo leading to p38 MAPK activation via the scaffold protein JLP, and MKK6 kinase (Takaesu et al. J Cell Biol 175: 383). Once activated, p38 MAPK phosphorylates Mef2d leading to the targeting of the Ash2L methyltransferase complex to muscle specific promoters. The methyltransferase complex then establishes the epigenetic H3K4me3 mark required for high-level expression of developmentally regulated genes.
Selected Publications
A. Aziz, Q-C. Liu, and F.J. Dilworth. Regulating a master regulator: establishing tissue-specific gene expression in skeletal muscle. Epigenetics 5: in press, 2010.
S. Seenundun, S. Rampalli, Q-C. Liu, A. Aziz, C. Palii, S.H. Hong, A. Blais, M. Brand, K. Ge, and F.J. Dilworth. UTX-mediated demethylation of H3K27me3 at muscle-specific genes during myogenesis. EMBO Journal 29: 1401-1411, 2010.
B.D. Larsen, S. Rampalli, L.E. Burns, S. Brunette, F.J. Dilworth, and Lynn A. Megeney. Caspase 3/Caspase Activated DNase Promote Cell Differentiation by Inducing DNA Strand Breaks. Proc Natl Acad Sci USA 107: 4230-4235, 2010.
Publication recommended by Faculty of 1000 Biology
C-P. Chaturverdi, A. Hosey, C. Palii, C. Perez-Iratxeta, Y. Nakatani, J.A. Ranish, F.J. Dilworth, and M. Brand. Dual role for the methyltransferase G9a in maintenance of -globin gene transcription in adult erythroid cells. Proc Natl Acad Sci USA 106: 18303-18308, 2009.
Z. Yang, K. MacQuarrie, E. Analau, A.E. Tyler, F.J. Dilworth, Y. Cao, S.J. Diede, and S.J. Tapscott. MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state. Genes & Development 23 : 694-707, 2009.
Publication recommended by Faculty of 1000 Biology
M. Brand, S. Rampalli, C-P. Chaturverdi, and F.J. Dilworth. Analysis of epigenetic modifications of chromatin at specific gene loci by native chromatin immunoprecipitation (N-ChIP) of nucleosomes isolated using hydroxyapatite chromatography. Nature Protocols 3: 398-409, 2008.
I.W. McKinnell, J. Ishibashi, F. LeGrand, V.J.G. Punch, G. Addicks, J.F. Greenblatt, F.J. Dilworth, and M.A. Rudnicki. Pax7 activates myogenic genes by recruitment of a histone methyltransferase complex. Nature Cell Biology 10: 77-84, 2008.
Publication recommended by Faculty of 1000 Biology
S. Rampalli, L. Li, E. Mak, K. Ge, M. Brand, S.J. Tapscott, and F.J. Dilworth. p38 MAPK signaling pathway regulates recruitment of Ash2L-containing methyltransferase complexes to specific genes during differentiation. Nature Structural and Molecular Biology 14: 1150-1156, 2007.
Publication recommended by Faculty of 1000 Biology
C. Demers, J.A. Ranish, G. Juban, P. Lai, F. Morle, R. Aebersold, F.J. Dilworth, M. Groudine, and M. Brand. Activator-mediated recruitment of the MLL2 methyltransferase complex to the -globin locus. Molecular Cell 27: 573-584, 2007.
R. Pavri, B. Lewis, T-K. Kim, F.J. Dilworth, H. Erdjument-Bromage, P. Tempst, G. de Murcia, R. Evans, P. Chambon, and D. Reinberg. PARP-1 determines specificity in a retinoid signaling pathway via direct modulation of mediator. Molecular Cell 18: 83-96, 2005.
Publication recommended by Faculty of 1000 Biology
F.J. Dilworth, K. Seaver, A. Fishburn, S. Htet, and S.J. Tapscott. In vitro transcription system delineates the distinct roles of the coactivators pCAF and p300 during MyoD/E47-dependent transactivation. Proceedings of the National Academy of Science USA 101 : 11593-11598, 2004.
F.J. Dilworth, and P. Chambon. Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription. Oncogene 20: 3047-3054, 2001.
F.J. Dilworth, C. Fromental-Ramain, K. Yamamoto, and P. Chambon. ATP-driven chromatin remodeling activity and histone acetyltransferases act sequentially during transactivation by RAR/RXR in vitro. Molecular Cell 6: 1049-1058, 2000.
Work in our laboratory is funded by:
Canadian Institutes of Health Research
Canadian Research Chairs
Canadian Foundation for Innovation
Ontario Ministry of Research and Innovation
Current Lab Members
Arif Aziz - Post-Doctoral Fellow - araziz@ohri.ca
Tara Crawford - Honour's Thesis Student - tcrawford@ohri.ca
Tarunpreet Dhaliwal - Graduate Student - tdhaliwal@ohri.ca
LiFang Li - Lab Manager/Technician - lili@ohri.ca
Qi-Cai Liu - Post-Doctoral Fellow - qliu@ohri.ca
Patricia Rakopoulos - Graduate Student - prakopoulos@ohri.ca
Kiarash Rokui - Honour's Thesis Student - tcrawford@ohri.ca
Soji Sebastian - Post-Doctoral Fellow - ssebastian@ohri.ca
Kulwant Singh - Post-Doctoral Fellow - kusingh@ohri.ca
Former Trainees
Shravanti Rampalli (PDF) - Post-Doctoral Fellow (Bhatia Lab - Stem Cell and Cancer Research Institute, Hamilton, ON)
Shayesta Seenundun (PDF) - Biologist/Evaluator (Health Canada)
Xin (Cindy) Chen (Co-op Student) - PhD Student (University of Toronto)
Sarah Hewitt (Co-op Student) - Masters Student (University of Ottawa)
How to apply to the laboratory
Post-Doctoral Fellows - Please send a copy of your CV (including list of publications), and a short paragraph describing your career goals.
Graduate Students - Please send a copy of your CV, your transcripts, and a short paragraph describing your career goals.
