Research
Biology of lysine methylation and cancer : E. Julien

Research topics

 

A main issue in biology is to understand how cells of our body can be so different even though they all have the same genetic heritage. Over the past two decades, many discoveries have shown that the interpretation of the genetic code depends on another code, called the epigenetic code. Indeed, access to the DNA molecule, the carrier of genetic information, is finely regulated thanks to the specific organization of DNA in a very complex structure, called chromatin. The basic unit of chromatin is the nucleosome, which consists of an octamer of histones (H2A, H2B, H3 and H4) around which the DNA molecule is wound. Chromatin is subject to numerous chemical modifications, called epigenetic modifications, such as DNA methylation or post-translational modifications (methylation, acetylation, phosphorylation...) of histone proteins. By defining distinct chromatin domains along the genome, these modifications modulate the state of compaction of the chromatin and thus the accessibility of the genome to the various molecular machineries that use DNA as a matrix (transcriptions, replication and repair).

 

                                         

 

It is widely established that the chromatin structure and its epigenetic modifications play a decisive role in cell identity/fate and that their alterations contribute to the development of human diseases, including cancers. Nevertheless, changes in chromatin structure, unlike genetic modifications, are reversible and therefore constitute a very promising therapeutic target. The challenge therefore lies in the detailed understanding of epigenetic mechanisms, in order to offer new therapeutic perspectives in the treatment of cancer with the development of "epigenetic drugs", targeting the key factors of these epigenetic mechanisms. In addition, this research can pave the way for the identification of many biomarkers of diagnosis, prognosis and treatment response.

 

                           

 

In this context, our team is particularly interested in the signaling pathways induced by the enzymes responsible for the methylation of lysine 20 at the N-terminal tail of histone H4. To do this, we use advanced genomic and proteomic tools in both mammalian genetic models and Drosophila, a model of choice to characterize new epigenetic mechanisms and then study their roles in tumor cells. Our current research focuses on three main themes: (i) the role of lysine 20 methylation of histone H4 (H4K20) in genome replication and stability, (ii) the identification and characterization of non-histone substrates of H4K20-methylation enzymes and their interplay with cellular processes associated with cancer, and (iii) the discovery of new synthetic lethality combining chemical inhibitors against methylation enzymes in cancer cells.

 


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