Cell signaling pathways converge on post–translational modifications (PTMs) which play critical roles in regulating chromatin structure and gene expression. Histone PTMs constitute the “epigenetic code” influencing chromatin and transcription and lysine methylation in particular is emerging as a versatile and dynamic PTM that contributes to cellular differentiation programs. We are interested in understanding the role of Lysine methylation, of both histone and non-histone substrates, in a number of cellular scenarios.
SET-ting the scene with SMYD3
We study the role of the SMYD3 Lysine methyltransferase in the muscle differentiation program in human and mouse myoblasts and how it functions as an integrator of signaling pathways in the nucleus and in the cytoplasm. We are also interested in the role of SMYD3 in tumor progression and the regulation of metastatic gene programs.
PIN-ning down the Parasite
In parallel we study how infectious agents develop intricate mechanisms to hijack the genetic and epigenetic machinery of their host cells to change phenotypic states. We investigate how the intracellular parasite Theileria annulata hijacks host signaling pathways to maintain cell transformation. We recently identified epigenetic events in the host cell nucleus that are induced by the intracellular parasite and we also study epigenetic regulators of the parasite genome. The Theileria-infected leukocytes serve as a model to explore the plasticity of cellular phenotypes, the determinants of cell identities and the evolutionary strategies of interacting cellular systems.
Our main goals are:
– To characterize the role of the SMYD3 methyltransferase in muscle differentiation and cancer
– To identify nuclear and cytoplasmic Lysine methylation events in cell differentiation and proliferation
– To characterize mechanisms by which intracellular parasites hijack host signaling pathways to manipulate the host genome and epigeneome
Our experimental approaches:
We use comparative genomic and proteomic approaches to study the role of Lysine methylation at the molecular and cellular levels. We study cellular differentiation models and parasite-infected cells to link methylation events to changes in cellular phenotypes. We use a combination of genetic knock-down and overexpression strategies, combined with drug inhibition and a battery of phenotypic assays for cellular proliferation and differentiation.
1. Marsolier J, Perichon M, DeBarry JD, Villoutreix BO, Chluba J, Lopez T, Garrido C, Zhou XZ, Lu K, Fritsch L, Ait-Si-Ali S, Mhadhbi M, Medjkane S*, Weitzman JB*. Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation. (2015) Nature 520:378-82.
2. Weitzman MD*, Weitzman JB*. What’s the damage? The impact of pathogens on pathways that maintain host genome integrity. (2014) Cell Host & Microbe 15:283-294.
3. Medjkane S, Perichon M, Marsolier J, Dairou J, Weitzman JB. Theileria induces oxidative stress and HIF1α activation that are essential for host leukocyte transformation (2013) Oncogene doi: 10.1038/onc.2013.134
4. Marsolier J*, Pineau S*, Medjkane S, Perichon M, Yin Q, Flemington E, Weitzman MD, Weitzman JB. OncomiR addiction is generated by a miR-155 feedback loop in Theileria-transformed leukocytes. (2013) PLoS Pathogens 9(4):e1003222.
5. Cock-Rada AM*, Medjkane S*, Janski N, Yousfi N, Perichon M, Chaussepied M, Chluba J, Langsley G, Weitzman JB. SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. (2012) Cancer Research 72:810-20.