MSCA Postdoctoral Fellowship - The Role of m6A Methylation in Response to Genotoxic Stress and [...]

European Commission; France; Sur place; EUR 35 000 - 45 000; Plein temps

Résumé du poste

Une position de postdoctorant est ouverte au sein du laboratoire LRTOX pour étudier le rôle de la méthylation m6A dans la réponse à l'irradiation ionisante. Les candidats devront avoir un doctorat et démontrer d'excellentes compétences en recherche expérimentale et en analyse de données. Ce fellowship dans le cadre de la Horizon Europe MSCA offre un environnement collaboratif et des ressources exceptionnelles, avec une date limite d'application au 31 juillet 2025.

Prestations

Accès à des infrastructures de recherche

Environnement de travail collaboratif

Qualifications

• PhD ou équivalent requis.
• Avoir un maximum de 8 ans d'expérience en recherche.
• Maîtrise de l'anglais exigée.

Responsabilités

• Investiguer le rôle de la méthylation m6A dans la réponse aux stress génotoxiques.
• Évaluer les modifications de méthylation dans un modèle murin.
• Travailler en collaboration pour écrire des propositions conjointes.

Connaissances

Recherche expérimentale

Analyse de données

Rédaction scientifique

Formation

Doctorat en biologie ou domaine similaire

Description du poste

Organisation/Company ASNR Department PSE-SANTE/SESANE Research Field Biological sciences » Biology Researcher Profile First Stage Researcher (R1) Positions Postdoc Positions Country France Application Deadline 31 Jul 2025 - 17:00 (Europe/Paris) Type of Contract Temporary Job Status Full-time Is the job funded through the EU Research Framework Programme? Horizon Europe - MSCA Is the Job related to staff position within a Research Infrastructure? No

Offer Description

The LRTOX laboratory of the French Authority for Nuclear Safety and Radioprotection (ASNR) welcomes applicants for a Marie S. Curie Action (MSCA) Postdoctoral Fellowship for the following research project:

The Role of m6A Methylation in Response to Genotoxic Stress and in Cancer
Supervisor: Guillaume Varès

In response to ionizing radiation (IR) exposure, cells trigger a variety of complex and coordinated mechanisms, which include DNA Damage Response (DDR), the control of cellular proliferation or apoptosis induction. IR exposure might lead to genomic instability, chromosomal aberrations and cancer. However, while the effects of high doses of IR are well understood in a variety of models, including colon cancer[1], a wide variety of issues and questions remain concerning low dose effects, for which there is no consistent evidence yet of increased cancer incidence[2]. It is therefore crucial to better understand the molecular responses to low dose IR (LDR) in order to improve the assessment of cancer and non-cancer risks.

Gene regulation was previously thought to be driven mainly by the changes in transcription activation and repression under the control of transcription regulators. However, there is mounting evidence that post-transcriptional mechanisms, including the control of RNA translocation, splicing, translation, decay and stability, play a crucial role in shaping responses during physiological processes (development, immunity, stress responses, etc.). RNA stability regulation has been associated with the pathophysiology of various diseases[3–5]. This mechanism is especially important when rapid changes of gene expression are necessary, such as for controlling rhythmic gene expression in the circadian clock machinery[6].

In recent years, N6-methyladenosine (m6A) RNA modification has gained a lot of attention as a major regulatory marker controlling diverse aspects of RNA metabolism and function, including: alternative splicing, structure switching, export, miRNA maturation, stability, translation, m7G-independent translation and decay[7]. The presence and role of m6A on RNA are determined by the interplay between m6A-interacting proteins: methyltransferases ( writers : METTL3, METTL14, etc.), demethylases ( erasers : FTO, ALKBH5, etc.) and m6A-binding proteins ( readers : YTHDF1, YTHDC2, etc.).

m6A methylation can regulate the expression of oncogenes and control cell differentiation, proliferation and migration, stem-like phenotype and tumor microenvironment[8]. Oncogenic properties of m6A regulating proteins have been reported in a number of cancer models. In colon cancer, METTL3 is over-expressed and promotes translation of EGFR and the Hippo pathway effector TAZ[9]. YTHDF1 is induced by c-Myc and is over-expressed in colon cancer, leading to cancer cell proliferation and resistance to anticancer drugs[10].

The detailed role of m6A modifications in radiation biology is still poorly known but is currently under intensive investigation[11]. m6A-related radiation-sensitive biomarkers (such as Ncoa4 , Ate1 and Fgf22 ) exhibit persistent dose-dependent m6A methylation levels and may serve as biomarkers of radiation exposure[12]. m6A methylation may also be used to predict radiation sensitivity[13] or to develop new treatment strategies[14].

Recently, it was shown that it is possible to detect RNA modifications using long-read direct RNA sequencing by comparing an experimental test condition with a control condition containing no RNA modifications after knock-down of the METTL3 methyltransferase[15]. However, given the described effects of METTL3 on DDR and carcinogenesis, approaches relying on inhibiting its expression to identify m6A methylation sites may not be the most suitable for studies investigating time course of m6A regulation after stress or during carcinogenesis. Alternatively, it is possible to obtain a de novo profile of m6A sites by detecting increased mismatches around modified RNA bases[16] or by focusing on specific types of sequences through fraction modification values[17].

Here, we propose to investigate the dynamics and regulation of m6A methylation after exposure to low doses of ionizing radiation in a murine cell model through the following methodological and research aims:

• To map RNA modifications transcriptome-wide using long-read sequencing (Nanopore technology) using a METTL3 shRNA-based approach[15] and an alternative de novo approach within filtered DRACH [1] motifs[17] and/or m6RIP-seq[18] + gene-specific m6A-RT-qPCR[19].
• To evaluate and characterize the role of m6A methylation in regulating the RNA stability and metabolism in colon carcinogenesis, using a model developed in our laboratory, that is, organoids derived from an APCf/f KRAS+/f CDX2-Cre-ERT2 (KPC:APC) inducible colon cancer model[20]. After tamoxifen administration KPC:APC mice develop tumors that mimic the histological and molecular characteristics of human colorectal cancer.
• To measure m6A methylation modifications (and potentially other RNA methylation modifications) in the colonic tissues of the KPC:APC mouse exposed to low dose radiation exposure in relation to colon carcinogenesis and/or in cell lines after radiation exposure.

Besides an excellent access to infrastructure resources (histology, molecular biology, bioinformatics, etc.), the laboratory offers a supportive and collaborative environment, with multiple opportunities for personal growth.

[1] Consensus motif for METTL3/METTL14 methyltransferases (D = A, G or T; R = A or G; H = A, C or U)

References:

1. Sugiyama H, Misumi M, Brenner A, Grant EJ, Sakata R, Sadakane A, et al. Radiation risk of incident colorectal cancer by anatomical site among atomic bomb survivors: 1958–2009. Int J Cancer. 2020;146:635–45.

2. Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, et al. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci U S A. 2003;100:13761–6.

7. Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res 2018 286. 2018;28:616–24.

9. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m6A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol Cell. 2016;62:335–45.

12. Chen H, Zhao X, Yang W, Zhang Q, Hao R, Jiang S, et al. RNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation. Nat Commun 2023 141. 2023;14:1–16.

13. Zeng Z, Zhang J, Li J, Li Y, Huang Z, Han L, et al. SETD2 regulates gene transcription patterns and is associated with radiosensitivity in lung adenocarcinoma. Front Genet. 2022;13:935601.

14. Zhang Y, Gu W, Shao Y. The therapeutic targets of N6-methyladenosine (m6A) modifications on tumor radioresistance. Discov Oncol 2023 141. 2023;14:1–14.

16. Liu H, Begik O, Lucas MC, Ramirez JM, Mason CE, Wiener D, et al. Accurate detection of m6A RNA modifications in native RNA sequences. Nat Commun 2019 101. 2019;10:1–9.

19. Castellanos-Rubio A, Santin I, Olazagoitia-Garmendia A, Romero-Garmendia I, Jauregi-Miguel A, Legarda M, et al. A novel RT-QPCR-based assay for the relative quantification of residue specific m6A RNA methylation. Sci Reports 2019 91. 2019;9:1–7.

20. Maitra R, Thavornwatanayong T, Venkatesh MK, Chandy C, Vachss D, Augustine T, et al. Development and Characterization of a Genetic Mouse Model of KRAS Mutated Colorectal Cancer. Int J Mol Sci. 2019;20:5677.

Where to apply

E-mail [e-mail]

Requirements

Research Field Biological sciences » Biology Education Level PhD or equivalent

Specific Requirements

If you wish to apply and submit a joint project, please send an email to [e-mail] , with your CV, cover letter and at least one recommendation letter.

The selected candidate and his/her supervisor will be responsible for writing a joint proposal on their project topic, which will be submitted to the Horizon Europe MSCA Postdoctoral Fellowship call and evaluated by experts appointed by the European Commission. Our internal application deadline is 31 July 2025, with the expectation that the selected candidate and his/her supervisor will complete a proposal by early September.

Languages ENGLISH Level Excellent

Research Field Biological sciences » Biology

Additional Information

Eligibility criteria

- Candidates must be in possession of a doctoral degree before the call deadline (10 Sept. 2024) and have a maximum of 8 years full-time equivalent experience in research.

- “Mobility rule”: candidates must NOT have resided or carried out their main activity in France for more than 12 months in the 36 months immediately before the call deadline. Candidates can be from any nationality.

Work Location(s)

Number of offers available 1 Company/Institute Autorité de Sûreté Nucléaire et de Radioprotection (ASNR) Country France City Fontenay-aux-Roses Postal Code 92262 Street 31 avenue de la Division Leclerc Geofield