CE12 - Génétique, génomique et ARN

Role of the lysine methyltransferase PR-Set7/SET8 in gene regulation through non-histone signaling – LysMeth

Submission summary

Histone methylation by lysine methyltransferases (KMTs) is known to fundamentally regulate chromatin structure and functions. However, these enzymes have also non-histone substrates, which extend their functions beyond the histone code. Yet, despite the fundamental roles of these enzymes and their contribution to human diseases, their non-histone substrate specificity still remains poorly understood. Unraveling the lysine methylation signaling of non-histones substrates constitutes therefore an emerging research field that can open up important insights into the regulation of cell identity and fate. In this regard, our proposal aims to unravel the transcriptional role of the KMT PR-Set7 in gene regulation through non-histone signaling. Responsible for the mono-methylation of the histone H4 at lysine 20 (H4K20me1), PR-Set7 is an evolutionary-conserved KMT associated with human pathologies and that is essential for cell proliferation and the maintenance of genome stability. Over the last years, we and other labs demonstrated that PR-Set7-mediated H4K20 methylation contributes to the regulation of many DNA transactions, including the licensing of DNA replication origins, the compaction of chromatin and DNA repair mechanisms. Based on numerous preliminary data, we beleive that PR-Set7 also exerts critical transcriptional functions via the methylation of non-histone substrates. Apart from the tumour suppressor p53, the identity of these substrates and the consequences of their methylation have yet to be identified and characterized. In this regard, we have evidences that PR-Set7 is a positive regulator of cell-cycle genes network and that this function involves a specific interplay with the ISWI chromatin-remodeling complex NURF, in which the subunit NURF38 could be a novel PR-set7 substrate. Conversely, ISWI could behave as a decoy substrate for PR-Set7, modulating its substrate specificity on chromatin. Our preliminary data also suggest that the transcriptional function of PR-set7 and its interplay with ISWI/NURF are conserved in human cells and could be critical for cancer cell proliferation and survival. This is notably the case in multiple myeloma (MM), where the up-regulation PR-set7 appears as an adverse prognosis factor in MM patients.
Based on these data and using both Drosophila and human MM cells as model systems, our proposal has three main objectives: (i) to unravel the H4K20-independent transcriptional roles of PR-Set7 and its interplay with ISWI/NURF chromatin remodeling functions; (ii) To investigate how these transcriptional functions could contribute to cell proliferation/survival in normal and cancer cells and (iii) to identify and characterize the non-histones substrates by which this cancer-related KMT impacts on gene expression programs and cell fate. The impact and benefits of this project are multiple. First of all, PR-Set7 and ISWI are two essential chromatin-modifying enzymes associated with human pathologies (notably cancer) and whose functions in the regulation of genes are still very poorly understood and need to be further investigated. This project will also highlight a new regulatory role of ISWI on the activity of PR-Set7, which in turn, by methylating this complex, could constitute a new chromatin regulatory mechanism. Such interference between the activities of PR-Set7 and ISWI is clearly an emerging and exciting concept to explore regarding the concerted roles of these enzyme families on chromatin organization and gene regulation. Another impact of our project is the development of top-notch MS-based proteomic approaches for identification and quantification of methylated proteins and methyl binding interactors, and which will be applicable to any other methyltransferases. Finally, the study of the transcriptional functions of PR-Set7 and its non-histone substrates, including p53, will also be of great importance for human health, given the predominant role of this enzyme in cancer pathologies.

Project coordination

Eric Julien (Institut de Recherche en Cancérologie de Montpellier)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IRCM Institut de Recherche en Cancérologie de Montpellier
Biomedical Center (BMC) / Chromatin Remodeling laboratory
BGE BIOLOGIE A GRANDE ECHELLE
IAB Institut pour l'Avancée des Biosciences

Help of the ANR 469,551 euros
Beginning and duration of the scientific project: December 2020 - 48 Months

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