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Recent genomic sequencing and transcriptome analysis in a vast variety of cancers have revealed that a large number of chromatin modifiers and chromatin-binding proteins are found mutated or misexpressed in cancer cells. While known to play key roles in the maintenance of genome structure and functions, these largely unanticipated mutation and/or misexpression findings could illuminate newly recognized epigenetic mechanisms potentially central to the genesis of cancer. By developing targeted approaches in both mammalian and Drosophila genetic models, the aim of our group is to understand the function of cancer relevant gene families involved in chromatin-associated signaling pathways, with a particular focus on the family of lysine methyltransferases that regulate nuclear and epigenetic processes during the cell cycle.
Our current research is developed around two themes:
1. Biological functions of methyltransferases involved in histone H4-lysine 20 methylation, one of the broadest histone modification displaying dynamic changes during the cell cycle and often misregulation in cancer cells. Notably, we investigate the functions of the methyltransferase PR-Set7, which is the only enzyme known to generate H4-K20 monomethylation in metazoans.
2. Roles of lysine methyl-binding MBT (Malignant Brain Tumor) proteins in development and cancer. The MBT protein family has been linked to important transcriptional regulatory pathways, such as E2F/Rb and Polycomb-mediated repression, and and some of these proteins display mutations and/or aberrant expression in hematopoietic malignancies, breast, lung and ovarian cancer. However, the role of MBT proteins in tumorigenesis and their connection with lysine methylation pathways remain to be elucidated.
Zouaz A, Fernando C, Perez Y, Sardet C, Julien E, Grimaud C. Cell-cycle regulation of non-enzymatic functions of the Drosophila methyltransferase PR-Set7. Nucleic Acids Res. 2018 Jan 24. doi: 10. 1093/nar/gky034.
Brustel J, Kirstein N, Izard F, Grimaud C, Prorok P, Cayrou C, Schotta G, Abdelsamie AF, Déjardin J, Méchali M, Baldacci G, Sardet C, Cadoret JC, Schepers A, Julien E. Histone H4-K20 tri-methylation at late-firing origins ensure timely heterochromatin replication. EMBO J. 2017 Aug 4. pii: e201796541. doi: 10.15252/embj.201796541. [Epub ahead of print]
Williams DE, Izard F, Arnould S, Dalisay DS, Tantapakul C, Maneerat W, Matainaho T, Julien E, Andersen RJ. Structures of Nahuoic Acids B to E Produced in Culture by a Streptomyces sp. Isolated from a Marine Sediment and Evidence for the Inhibition of the Histone Methyl Transferase SETD8 in Human Cancer Cells by Nahuoic Acid A. J Org Chem. 2016 Jan 27. [Epub ahead of print]
Rodier G, Kirsh O, Baraibar M, Houlès T, Lacroix M, Delpech H, Hatchi E, Arnould S, Severac D, Duboix E, Cramal J, Julien E, Friguet B, Le Cam L & Sardet C. The transcription factor E4F1 coordinates CHK1-dependent checkpoint and mitochondrial functions. Cell Rep. 2015 Apr 14; 11 (2):220-33. doi:10. 1016/j. celrep. 2015.03.024. Epub 2015 Apr 2.
Brustel J, Tardat M, Kirsh O, Grimaud C and Julien E. (2011) Coupling mitosis to DNA replication. The emerging role of the lysine methyltransferase PR-Set7 (2011). Trends in Cell Biology. 21 :452-60.