Professor, Department of Physiology and Pathophysiology
Staff Scientist, St Boniface General Hospital
Scientific Director, MatriNET network (Matrix and Tissue Remodeling Network) – we will submit in the 2017 competition
Epigenetics, heart disease and cardiac fibrosis
Epigenetics refers to changes in gene expression that does not involve changes to the underlying DNA sequence. Our lab is particularly interested in how cells in the heart that synthesize extracellular matrix (matrix) undergo phenoconversion without changes in genotype. Disease states such as heart failure after myocardial infarction may influence epigenetic modifications in cells, and these may lead to phenoconversion of normally quiescent cells such as cardiac fibroblasts to cardiac myofibroblasts, which are hypersynthetic and physically contractile. Too much matrix is necessarily a “bad thing” and is synonymous with cardiac fibrosis and heart failure.
Members of our lab have discovered that Ski (a phylogenetically ancient protein that inhibits TGF-β and Smad signaling) may reverse fibroblast phenoconversion when overexpressed in cells. We would like to investigate the epigenetic mechanisms that control this class of proteins, and are specifically interested in processes that govern SUMOylation, phosphorylation, and ubiquitonation of Ski and Sno proteins. Thus we would design experiments to help us track:
1. The addition of a Small Ubiquitin-like Modifier (SUMO) protein to Ski as the target. As this
modification is involved in trafficking proteins to the nucleus, we would like to know
whether this plays a role in compartementalizing Ski in the cytosol in cells active in
chronic wound healing.
2. Whether ubiquitonation is important for regulating Ski in myofibroblasts in the failing
heart. The addition of one or a chain of ubiquitin proteins to a protein target. It often
targets the protein for degradation but can also alter its localization, conformation, or
3. Whether phosphorylation of serine or threonine residues of Ski is relevant to its cellular
function, by altering protein conformation.
4. Deletion or induction of Ski or Sno using CRISPR technology. We would use this genome
editing system to target Ski or Sno DNA regions of interest by a specific guide RNA linked
to Cas9 to induce DNA double strand breaks. It may be particularly useful in avoiding
off-target effects, and for simplicity of implementation.
Our goal is to gain a better understanding of the cellular control of Ski and Sno, and thus understand this mode of fibroblast phenoconversion, and subsequent induction of cardiac fibrosis in heart failure.