Research Summary

In multicellular organisms, the unique transcriptional program executed by each cell determines cellular identity. Indeed aberrant gene expression is a causal factor in many common human diseases, including cancer. While the availability of appropriate transcriptional activators or repressors determines whether a gene is transcribed, alteration of chromatin structure plays an important role in maintaining gene expression states. Chromatin is a nucleoprotein structure, consisting of DNA, histones, and non-histone proteins, which packages DNA in the eukaryotic nucleus. Our research focuses on multi-protein complexes which post-translationally modify histones. We are interested in determining how these complexes are targeted to specific regions of the genome, and the functional consequences of this targeting. Our research uses a combination of molecular biology and bioinformatics to study the roles played by histone chaperones, histone variants, and histone post-translational modifications in preserving active gene expression patterns. We are currently using the yeast, S. cerevisiae, as a model organism due to the ease of genetic manipulation of this organism, and the fact that all of the components in the paths under study are conserved from yeast to human.

Bio

BSc, University of Victoria, 1992
PhD, University of Victoria, 1998
CIHR Post-Doctoral Fellow, Pennsylvania State University, 1998-2003

Awards

2006 CIHR New Investigator Award
2004 Michael Smith Foundation for Health Research Scholar Award

Publications
  1. Maltby VE, Martin BJ, Brind’Amour J, Chruscicki AT, McBurney KL, Schulze JM, Johnson IJ, Hills M, Hentrich T, Kobor MS, Lorincz MC, Howe LJ. Histone H3K4 demethylation is negatively regulated by histone H3 acetylation in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18505-10. doi: 10.1073/pnas.1202070109. Epub 2012 Oct 22.
  2. Maltby VE, Martin BJ, Schulze JM, Johnson I, Hentrich T, Sharma A, Kobor MS, Howe L. Histone H3 lysine 36 methylation targets the Isw1b remodeling complex to chromatin. Mol Cell Biol. 2012 Sep;32(17):3479-85. doi: 10.1128/MCB.00389-12. Epub 2012 Jul 2.
  3. Chruscicki, A., Macdonald, V. E., Young, B. P., Loewen, C. J. R. & Howe, L. J. Critical determinants for chromatin binding by Saccharomyces cerevisiae Yng1 exist outside of the plant homeodomain finger. Genetics 185, 469–477 (2010).
  4. Choi, J. K. & Howe, L. J. Histone acetylation: truth of consequences? Biochem. Cell Biol. 87, 139–150 (2009).
  5. Macdonald, V. E. & Howe, L. J. Histone acetylation: where to go and how to get there. Epigenetics 4, 139–143 (2009).
  6. Choi, J. K., Grimes, D. E., Rowe, K. M. & Howe, L. J. Acetylation of Rsc4p by Gcn5p is essential in the absence of histone H3 acetylation. Mol. Cell. Biol. 28, 6967–6972 (2008).
  7. Shi, X. et al. Proteome-wide analysis in Saccharomyces cerevisiae identifies several PHD fingers as novel direct and selective binding modules of histone H3 methylated at either lysine 4 or lysine 36. J. Biol. Chem. 282, 2450–2455 (2007).
  8. Martin, D. G. E. et al. The Yng1p plant homeodomain finger is a methyl-histone binding module that recognizes lysine 4-methylated histone H3. Mol. Cell. Biol. 26, 7871–7879 (2006).
  9. Martin, D. G. E., Grimes, D. E., Baetz, K. & Howe, L. J. Methylation of histone H3 mediates the association of the NuA3 histone acetyltransferase with chromatin. Mol. Cell. Biol. 26, 3018–3028 (2006).
  10. Fish, R. N. et al. Genetic interactions between TFIIF and TFIIS. Genetics 173, 1871–1884 (2006).
  11. Li, B., Howe, L. J., Anderson, S., Yates, J. R. & Workman, J. L. The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymerase II. J. Biol. Chem. 278, 8897–8903 (2003).
  12. Nourani, A. et al. Opposite role of yeast ING family members in p53-dependent transcriptional activation. J. Biol. Chem. 278, 19171–19175 (2003).
  13. Howe, L. J. et al. Yng1p modulates the activity of Sas3p as a component of the yeast NuA3 Hhistone acetyltransferase complex. Mol. Cell. Biol. 22, 5047–5053 (2002).
  14. Neely, K. E., Hassan, A. H., Brown, C. E., Howe, L. J. & Workman, J. L. Transcription activator interactions with multiple SWI/SNF subunits. Mol. Cell. Biol. 22, 1615–1625 (2002).
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