The myocyte enhancer factor 2 (MEF2) family of transcription factors plays important roles during muscle differentiation as well as in different programs of non-muscle cells. Covalent modification has emerged as an important mechanism for regulating MEF2 function. The goal of my thesis project was to identify novel post-translational modifications that modulate MEF2 transcriptional activity and to determine whether histone deacetylases coordinate these modifications. I first demonstrated that MEF2D is modified by the ubiquitin-like protein SUMO. Sumoylation of MEF2D at a single residue, lysine 439, inhibits the myogenic activity of this transcription factor. Fascinatingly, histone deacetylase 4 (HDAC4) potentiates the sumoylation of MEF2D. In addition, HDAC4 stimulates this modification by promoting phosphorylation of serine 444 of MEF2D. In support of this, phosphorylation of serine 444 is required for sumoylation at lysine 439. Thus, I have identified a phospho-sumoylation switch that turns on and off MEF2-dependent transcription. Moreover, I found that MEF2D is subject to lysine acetylation catalyzed by the acetyltransferases PCAF and p300. Unexpectedly, HDAC3, but not HDAC4 and homologs, reverses this modification. Moreover, HDAC3 reverses autoacetylation of p300 and PCAF. Altogether, these results indicate that HDAC3 and HDAC4 are important regulators with distinct role in controlling MEF2 modifications, and further suggest that multiple HDACs cooperate to achieve efficient control of MEF2-dependent transcription and that disruption of MEF2-HDAC interaction may lead to pathological conditions like cardiac hypertrophy, coronary artery disease and lymphoblastic leukemia.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.102503 |
| Date | January 2006 |
| Creators | Grégoire, Serge. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | © Serge Grégoire, 2006 |
| Relation | alephsysno: 002565498, proquestno: AAINR27783, Theses scanned by UMI/ProQuest. |
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