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Analysis Of The Transcriptional Basis Of Natural Transdifferentiation In C. Elegans

Reference : PhD Sophie JARRIAULT

Publication de l'offre : 5 avril 2016

Development is viewed as a hierarchical process during which the vast majority of cells progressively restrict their cellular potential to adopt a final specialised identity. In most cases this differentiated identity is maintained until the cell death. This had initially led to the idea that the differentiated identity could not be reversed. However, landmark studies in the last decade have shown that not only can a differentiated cell identity be
experimentally erased, but remarkably, that it can be naturally converted into a different cell type in vivo, a process called transdifferentiation. These studies have sparked new questions around the maintenance and reprogramming of the cellular identity. For example, how progressively is the initial identity erased? Can we define successive distinct expression programmes during the conversion? How are they controlled? These questions, core to the field, are at the heart of this PhD project. In the longer run, such knowledge will be key to improve our ability to manipulate the cellular identity and engineer safe remplacement cells for regenerative medicine.

Our team has shown that cell type conversion naturally occurs in the roundworm C. elegans. In particular, we have focused on the cell-type conversion of a rectal cell, called "Y", into a moto-neuron, called "PDA". This transdifferentiation event occurs naturally in all wild type worms, with 100% efficiency and invariant timing (PNAS 2008). This has provided a unique and much expected system in the field to study cell type conversion, as the
transparency and established lineage of the worm allows to anticipate and scrutinise transdifferentiation in vivo, in real time, at the single cell level. By studying one such single cell natural transdifferentiation event, our team has contributed answers to key questions in the field, such as insights on the transition and cellular steps involved, the identification of conserved nuclear factors crucial to the initiation of the process, or the relative importance and roles of transcription factors versus histone modifying factors for the dynamics and robustness of the conversion (PNAS 2008, Dev 2010, PNAS 2012, Science 2014). The next step is to determine which genes that determine the initial identity are switched off, and how, what expression
programme is on during the apparently dedifferentiated phase, and how and with what dynamics is PDA expression programme switched on.

The proposed PhD project aims at answering these questions, by joining the expertise of our team on these questions, central to our lab, and model, and the technical expertise of the Meister lab, needed to bypass current technical roadblocks.
Thus, the overall objective of this project is to uncover the transcriptional basis of transdifferentiation from an hypodermal into a neuronal identity and further characterize the function of these genes in maintenance and conversion of cell fates.

It will entail three aims:
1. Setup of robust, cell type specific and temporally controlled RNA polymerase II profiling in C. elegans.
2. Establish nuclei sorting using fluorescent markers (normalisation: comparison by RNA Seq to the transcriptoml profiling of whole Y cells, as
currently done in the Jarriault's lab).
3. Characterize the function of genes differentially expressed during transdifferentiation.

- WISHED SKILLS : The applicant will have an excellent undergraduate track record in Biology, preferably as a Developmental Biology and/or Genetic major. The applicant will have successfully obtained a Master in Science degree. A preliminary practical experience using C. elegans is a plus, but is
not requiered. However having experienced the daily work in a laboratory is recommended, and a high motivation and commitment is required.

- C. elegans genetics (mutant strains construction, microscopy, cells morphological identification, transgenics, etc)
- genomics (RNAi, promoters analysis)
- molecular biology (clonings, PCR, RNA synthesis, stainings, etc)
- informatics (sequence analysis, motifs recognition)
- design, planification and undertakings of experiments
- trouble shooting
- optimal management of time schedule
- results analysis and elaboration of hypothesis
- design of approaches to verify an hypothesis on a medium term perspective

Votre candidature

Date limite de candidature : 31 décembre 2016

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