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Study Of The Ner Factors Roles In The Regulation Of Gene Expression

Reference : PhD Nicolas LE MAY

Offer publication : April 5, 2016

Differential gene expression in multi-cellular organisms determines the cell-type specificity. However, gene expression can be jeopardized by genotoxic stress that challenges genome integrity and requires several DNA repair pathways to eliminate DNA damages. This suggests an important orchestration between the disparate processes of transcription and DNA repair. Such connection between transcription and DNA repair has been recently demonstrated by showing the recruitment of the NER factors XPC, CSB, XPA, XPG and XPF-ERCC1 at the promoter of activated genes.

Strikingly, these factors belong to the Nucleotide Excision Repair (NER) pathway that contributes to remove DNA lesions generated by bulky adducts including UV light. In transcription, the recruitment of these NER factors to the promoter of activated genes has been correlated with chromatin remodelling including histones post-translational modifications (PTMs), active DNA demethylation and chromatin rearrangements. However, their
precise roles remain elusive.

The characterization of the functions played by the NER factors is particularly relevant since their mutations originate severe genetic disorders such as Xeroderma Pigmentosum (XP). XP is characterized by an extreme sensitivity to UV rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun. XP patients develop severe sunburn after spending just a few minutes in the sun. By age 2, almost all of them
develop freckling of the skin in sun-exposed areas (such as the face, arms, and lips). While XP patients including develop multiple skin cancers (melanoma, squamous cell carcinoma), they may have also increased cancer susceptibility in many other tissues, including breast tissue and lung tissue sometimes with neurological issues. These pathologies have been primarily defined as DNA repair syndromes due to the inability of patient’s
cells to eliminate DNA lesions. However, studies during the last decade suggest that many phenotypes stem from transcriptional deregulations.

For this project, we aim to focus on XPA. Indeed, few reports have treated the XPA transcriptional role and its impact on the aetiology of XP-A patients. However, we have already observed that the recruitment of XPA is a prerequisite for the presence of XPG and XPF-ERCC1 and their related DNA breaks induction and active DNA demethylation on RARβ2. Moreover, we also showed that XPA could independently regulate histones
PTMs upon transcription. Finally, we have correlated a default RARβ2 expression in cells derived from XP-A patients with a deregulation of chromatin remodelling.

The goal of this project is to investigate the roles played by XPA in chromatin remodelling during the gene expression to relate it to the aetiology, in particular the relationship between the transcriptional deficiencies and the higher predisposition to develop cancers, of XP-A patients. We plan to firstly identify the XPA partners; especially those involved in histones PTMs regulation and further characterize them. Secondly, we will evaluate the transcriptional impacts of such interactions at the genome-wide scale. Based in our experience accumulated from our previous works on the other NER factors, we will compare our data for XPA in normal and pathological contexts. Thereby, several cells derived XP-A patients with the corresponding rescues will be analysed using genome-wide approaches including RNA-seq, ChIP-seq, mass spectrometry and further completed by biochemical or molecular approaches such as in vitro assays. We believe that the elucidation of the roles played by the NER factors in human cells is a wonderful challenge relevant for the cancer research and more globally the public health.

- WISHED SKILLS : We are looking for a student possessing strong thorical and expérimental backgrounds in transcription and epigenetic fields. Moreover, due our genome-wide and proteomic approaches, we would also like that the student has advanced bioinformatic knowledge.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : At the end of the PhD, the student will acquire the expertise to molercularly characterize genetic diseases besides performing fondamental research at the genome-wide scale. In addition, he will have develop and acquire state-of-the art in vitro and ex vivo technics. Finally, the accumulation and the treatment of data generated by our approaches will give the opportunity
to the student to manage bioinformatic tools and to learn how to synthesize a project. The PhD student will acquire the tools to manage and present his own project, share and teach his knowledge

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Application Deadline : Dec. 31, 2016

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