Ph.D students and Postdocs fellows interested in joining the laboratory should send us a cover letter, a full CV and the names of three referees in order to study national and international solutions for fellowships.
Send all requests to Claire Francastel
A rare disease to decode the functional link between DNA methylation and maintenance of centromere integrity
Claire FRANCASTEL group – Epigenetics and Cell Fate lab
(CNRS – Université de Paris – Paris-Rive gauche campus)
DNA methylation and centromere integrity are two important arms of genome maintenance, and their alterations are invariably associated with chromosomal instability and physiopathological conditions. The project aims at better understanding their functional links and the causal dimension on disease phenotypes.
Our team has contributed to place centromeric repeats transcription/transcripts at the heart of centromere maintenance. We also focus part of our research on a unique monogenic disease and remarkable case where compromised centromere integrity is directly linked to altered DNA methylation of the underlying repeats: the ICF syndrome. We have recently contributed to identify new ICF factors with unknown function, which represent unanticipated determinants of DNA methylation and centromere integrity.
Our team is recruiting a postdoc to further explore the functions, partners and genomic targets of the newly identified ICF factors, and to dissect the mechanisms that functionally link pathological DNA methylation, aberrant transcription, centromere loss of integrity and disease phenotypes. The project will involve the development of genome editing strategies, high throughput (epi)genomic and proteomic analyses, RNA studies and epifluorescence imaging.
Qualification. Highly motivated young researchers interested in the fundamental mechanisms that maintain genome integrity are encouraged to apply. We are seeking candidates with a broad set of technical and scientific skills, curiosity, autonomy, team spirit and strong work ethic. The applicant should have a strong background in molecular biology, epigenetic and RNA studies. Validated experience in genome editing will be a plus. Proficiency in English (written and oral) is required.
The successful applicant must have obtained, or be in the process of completing, a PhD in a relevant research area and a primary research paper in a peer-reviewed journal.
Our group belongs to the Epigenetics and Cell Fate unit located on the left-bank campus of the renowned Diderot University in Paris, France. We offer state-of-the-art equipment and a strong network of core facilities in a stimulating environment for multidisciplinary research.
Funding for the engineer/post-doctoral researcher is supported by an ANR grant for three years.
Application deadline is January 2020. Latest starting date April 2020.
How to apply. Applicants should send their CV, a motivation letter with a brief description of their scientific experience and interests and two/three reference letters to:
Dr Claire Francastel
UMR7216 – Epigénétique et Destin Cellulaire
Université Paris 7 Diderot
Bâtiment Lamarck – 4ème étage
Case Courrier 7042
35, rue Hélène Brion
M2 Proposal (1)
Identification of new regulatory RNAs that originate from alternative splicing of introns
The current vision of the RNA world, which distinguishes between coding and non-protein-coding RNAs (ncRNA), has recently been questioned with the demonstration that some RNAs could function both as mRNAs in the production of proteins and as inherently functional ncRNAs. We focus on a class of RNAs for which this duality is influenced by alternative splicing of small introns and dictates the fate of human progenitors. Beyond this duality, introns also represent a fraction of the transcriptome to which different regulatory functions have been assigned including release of small regulatory RNAs such as miRNA; the mirtron pathway produces pre-miRNA-like hairpin structures after debranching of the intron-lariat produced by splicing. Using computational and experimental approaches we have identified, in the human genome, new candidate mirtrons and bifunctional RNAs, i.e. in which disruption of the ORF by intron retention potentially generates a cognate ncRNA. These findings open up a whole new field of investigation in which questioning the type of molecule produced by a given genetic entity, and the factors that influence their biogenesis, becomes critical. Current challenges now consist in documenting the functional diversity generated by alternative splicing that is likely to unveil original aspects of transcriptional circuitries that govern stem cell fate.
- We will use Next Generation Sequencing to systematically identify novel multifunctional transcripts, including intron retaining non-coding isoforms and their cognate mRNA, and stable introns holding the potential to produce regulatory small RNAs, in the context of muscle stem cells. A bioinformatian (postdoc) is already working in the team.
- We will use bioinformatics tools to analyze these datasets and identify new small regulatory RNAs.
- We will experimentally validate these data by classical northern blot assays or stem-loop-PCR to detect introns and their associated small RNA in the context of muscle stem cells.
- Hubé F, Ulveling D, Sureau A, Forveille S, Francastel C. Short intron-derived ncRNAs. Nucleic Acids Res. 2017;45(8):4768-4781. -Hubé F, Francastel C. Mammalian introns: when the junk generates molecular diversity. Int J Mol Sci. 2015;16(3):4429-52.
- Francastel C, Hubé F. Coding or non-coding: Need they be exclusive? Biochimie. 2011;93(11):vi-vii.
- Ulveling D, Francastel C, Hubé F. Identification of potentially new bifunctional RNA based on genome-wide data-mining of alternative splicing events. Biochimie. 2011;93(11):2024-7.
- Ulveling D, Francastel C, Hubé F. When one is better than two: RNA with dual functions. Biochimie. 2011;93(4):633-44.
- Hubé F, Velasco G, Rollin J, Furling D, Francastel C. Steroid receptor RNA activator protein binds to and counteracts SRA RNA-mediated activation of MyoD and muscle differentiation. Nucleic Acids Res. 2011;39(2):513-25.
M2 Proposal (2)
Identification Une solution logicielle pour catégoriser les petits ARN non codants
Nous venons d’identifier une nouvelle source de production de petits ARN non codants régulateurs issus de l’épissage d’introns. Afin de les caractériser et de les catégoriser, un nouvel outil est nécessaire.
Il existe plusieurs serveurs web ou solutions logicielles permettant de détecter la présence d’un pre-miARN dans une séquence génomique. De même, les solutions pour identifier un ARNt ou un snoARN existent depuis plus de 10 ans, et malgré les découvertes récentes de nombreuses nouvelles séquences, et de caractéristiques particulières et spécifiques à chacun, aucun nouveau système d’identification n’a vu le jour. Enfin, aucune de ces solutions n’indiquent quelles sont les “chances” d’avoir un miARN plutôt qu’un snoARN. C’est pourquoi, nous souhaiterions développer une solution “tout-en-un”, reprenant les caractéristiques récentes de chaque petits ARN non codants, de les “scorer”, et de permettre une identification fiable de chacun d’entre eux. Il s’agira donc de récupérer les informations de la littérature, de classifier et pondérer les différents critères retenus, et de programmer (à l’aide de script ou programme déjà écrit sur le web) un logiciel complet et efficace. Des jeux de données connues (miRBase, snoRNAbase, etc…) serviront de jeux de tests.