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USF transcription factors as crucial skin-stress-mediators

Final Report Summary - USFMUV (USF transcription factors as crucial skin-stress-mediators)

Chemical, physical and biological hazards, including solar ultraviolet radiations, are major environmental skin risk triggering oncogenesis. Protection against UV-mediated DNA-damage is afforded by the tanning response. The molecular mechanism underlying the UV-response is in part dependant on gene expression modulation. Indeed, UV irradiation leads to the up-regulation of specific genes of the pigmentation pathway, which results in an overall increase in skin pigmentation. Although the cell type-specific bHLH-LZ activator Mitf transcription factor is required for constitutive pigmentation, we involved the p38-stress activated USF1 transcription factor for the tanning response. The comprehension of this transcription factors function is of great importance to establish what are the transcriptional regulation and mechanisms that occur at the skin level controlling its integrity.

The proposal linked to the integration of "Transcriptional Regulation and Oncogenesis" now "Gene Expression and Oncogenesis" in Rennes improved the general knowledge on USF transcription factors at the physiological and molecular levels by focusing on specific cellular processes, such as pigmentation, DNA repair and inflammation. Finally, in order to elucidate the function of bHLH-LZ transcription factors at the skin level, we focused on the different mechanisms that occur at both transcriptional and post-translational levels regulating USF transcription factors'function (activation of transcription, post-translational modifications such as phosphorylation sumoylation/acetylation, protein cooperation, and chromatin remodelling…).

To summarise the specific aims were:
1. To determine the global role of USF1 at skin level, after UV induction, by the use of the physiological USF1 KO mouse model.
2. To identify bHLH-LZ transcription factors (USF and Mitf) target genes in cancer cells, using a high throughput technology.
3. To correlate USF activity with stress mediated transcriptional regulation, protein modifications and epigenetic re-programming.

The main objective of the ERG project was to establish my scientific project in IGDR in Rennes, in order to obtained a permanent position as researcher in "Transcriptional Regulation and Oncogenesis" team led by Marie-Dominique Galibert. I obtained this year 2012, an academic position in Inserm public organism (CR1) based on this scientific project that would allow me to improve knowledge on the important role of USF-1 for UV response at skin level. This topic is particularly important notably because of the incidence of skin cancers and diseases related to environmental insults. While the two first years of the ERG project were mainly devoted to establish the different tools required for the analysis of the in vivo role of USF-1 transcription, we obtained promising results about its function in UV response on last months. By the use of mice model, we obtained results showed significantly different answers between wild type and USF-1 KO mice highlighting the specific role of USF-1 transcription factor in the regulation of the expression of major genes and processes at skin level upon UV. Thanks to this model we firstly involved the USF-1 transcription factor for the regulation of the expression of genes required for efficient DNA damage removal after UV through Nucleotide Excision Repair (NER). Loss of USF-1 is so associated with a lower DNA repair efficiency. This data led to one publication in Plos Genetics in 2012. Furthermore, we identified a new implication of the bHLH-LZ transcription factor in the regulation of cell cycle and proliferation at skin level in response to UV with an absence of cell cycle control in response to UV in the absence of USF-1. We characterised at molecular levels (transcriptomic analysis) and at cellular or skin levels in term of DNA repair and proliferation for which we already observed differences between mice. More interestingly, we demonstrated a close correlation between USF-1 transcription factor and p53 transcription factor. These results should lead rapidly to an important publication. We're really optimistic concerning these preliminary data about the crucial role of USF-1 transcription factor to regulate physiological processes at skin level and to maintaining genomic stability in response to UV.

This first part of the project has now to be correlated with the screening of bHLH-LZ target genes using high throughput technology (ChIPseq technology, Illumina) we attempt to address in collaboration with Irwin Davidson at IGBMC (Nancy) and Gilles Salbert in host institute. We expect to identify what are the USF-1 target genes and how promoter occupancy is regulated during UV response. Because USF and the melanocyte specific Mitf transcription factors, which belong to the same family, share the same consensus binding site (E box: CANNTG), we expect to identify common target genes and cooperation between these different factors for UV regulation of transcription.

The last objective of the project was not only to identify the role of USF-1 transcription factor during UV response at skin level, but also to understand how this factor is regulated depending on environmental stress. We already now following physiological cell-inductions with various chemical, physical or biological agents, USF-1 factor is phosphorylated by the stress-responsive p38 kinase leading to transcriptional activation of the USF-1 protein and subsequent increase of target gene expression. When the stimuli level is dramatically increased, compromising cell live, USF-1 becomes acetylated on lysine 199 preventing transcriptional activation. During the project, we also focused on other environmental conditions that could influence USF-1 level or activity (glucose, hypoxia…).

In conclusion, the obtained data during this project involved USF-1 transcription as a crucial factor for the early UV response at skin level. Because USF-1 constitutes an accurate sensor between skin and environment, with a tight regulation of its activity depending of stress level, and because it has been shown to be essential for DNA repair and cell proliferation control, USF-1 seems to be particularly important to maintain genomic stability at skin level under UV response. Loss of USF-1 could be correlated with skin diseases linked to solar irradiation in particular skin cancers, such as melanoma, that we're now looking for.

During the three last years, I set up this scientific project concerning the characterisation of the UV response at skin level with an important function for the USF-1 transcription factor. I have now to be in charge of this project in "Gene Expression and Oncogenesis team so to improve largely the knowledge about USF-1 (partners, modifications, target genes…) and to understand why this ubiquitous transcription factor is so important for skin homeostasis. This work will be done after integration of students (master dregree, PhD) during the next years, and through tight international collaborations.

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