30 bd Jean Monnet
Offre poste Doctorat en Immunologie / Bioinformatique - composante transcriptomique et épigénitque single-cell
Title: Characterization of thymic molecular factors responsible for the control of autoimmunity
The expression in the thymus of a full set of proteins, whose expression is normally restricted to peripheral tissues, and their presentation to the developing thymocytes is central in the establishment and maintenance of autoimmune tolerance, that is, the ability of the immune system to tolerate our body’s own constituents. Deregulation of this expression in the thymus leads to life-threatening autoimmune diseases, such as Type 1 Diabetes or the severe APECED syndrome caused by mutations in the AIRE gene whose coding protein has been shown to control a wide array of tissue-restricted proteins in the thymus. The project here aims to identify and characterize the molecular factors that control autoimmunity through the expression of “the self” in the thymus, in cooperation with or independently of AIRE, as well as factors that sustain the development and maturation of thymic cells to a stage where they become functional with the ability to express the self and control the development of thymocytes into non-autoreactive mature T cells.
The fellow will identify candidate factors through the generation and combined analysis of epigenetic single-cell (sc)ATAC-seq and transcriptomic scRNA-seq data of thymic cells in humans and Aire-KO mouse and rat models. The effect of the identified candidate factors on the expression of tissue-restricted proteins or thymic cell development will be tested by setting up a Crispr-Cas9 loss-of-function screen in a 3D co-culture system that enables the culture of fragile thymic cells and will be assayed by scRNA-seq. Finally, the most promising molecular factors will be selected and their effect assessed by gene deletion in a model of differentiation of iPS cells into mature thymic cells. The phenotype of the iPS-derived cells deleted for the selected candidate genes will be analyzed by single-cell transcriptomic and epigenetic methods. The loss of function of these iPSc-derived cells on thymocyte maturation will also be assessed by using ex-vivo systems of thymocyte development.
Candidates must hold a MSc diploma in Bioinformatics (transcriptomics) and having lab experience in immunology or cell biology. Highly motivated candidates holding a MSc diploma in Biology ideally with a major focus on immunology or cell biology and with knowledge and strong interest in bioinformatics/ transcriptomics are also encouraged to apply.
The PhD application deadline is 15/09/2020.
Candidates will be interviewed on site or by skype for final selection.
The PhD program will start in October 2020 for 3 years.
Documents required to apply:
- Curriculum Vitae
- Motivation letter
- At least two references and/or recommendation letters
- A statement of research experience and interests
Send to Dr Matthieu Giraud: email@example.com