Uncovering the role of R-loop-mediated epigenetic regulation in the response to anticancer therapies

R-loops are unusual nucleic acid structures consisting of an RNA/DNA hybrid and a single stranded DNA (ssDNA). They form during transcription and regulate key physiological processes, including gene expression. However, R-loop imbalance, caused by their unscheduled formation or failure to be timely resolved, can lead to genome instability and deregulated gene expression and has been involved in oncogenesis and cancer progression. R-loop imbalance is emerging as a common feature of cancer cells, including oncogene-driven cancers. However, R-loop role in the response to anticancer therapies remains poorly understood.

Our project aims to investigate the role of R-loops in driving transcriptional and epigenetic reprogramming in response to anticancer therapies. For this, we will identify the transcriptional and epigenetic changes depending on R-loops in response to anticancer treatment, the molecular mechanisms through which R-loops trigger these changes and how they translate into phenotypic plasticity at the single-cell level and genome-wide. Addressing these questions will advance our mechanistic understanding of the response to anticancer treatments paving the way for the development of therapeutic strategies aimed at improving the efficiency of anticancer therapies.

3 Selected Publications (PhD and Master students are underlined)

1) Geraud M*, Cristini A*, Salimbeni S*, Bery N, Jouffret V, Russo M, Ajello AC, Fernandez Martinez L, (…) Capranico G^#, Sordet O^#. TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks. Cell Rep. 2024 May 16;43(5):114214. *Co-first authors.

2) McCann JL*, Cristini A*, (…) Miller KM^#, Gromak N^# and Harris RS^#. APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer. Nat Genet. 2023 Oct;55(10):1721-1734. *Co-first authors.

3) Cristini A, Tellier A, Constantinescu F , Accalai C, Albulescu  LO, Heiringhoff R,  (…) Gromak N. RNase H2, mutated in Aicardi-Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation. Nat Commun. 2022 May 26;13(1):2961.

Main Techniques: We will employ a wide range of techniques, including cell culture, high-content and confocal imaging, live imaging, cell culture, CRISPR-Cas9, NGS (such as DRIP-seq, RNA-seq, ChIP-seq).

The student will join the subgroup “Transcription in Oncogenesis and Response to Treatment,” led by Agnese Cristini and funded by the ANR (webpage: https://www.crct-inserm.fr/en/exploring-transcription-in-oncogenesis-and-response-to-anticancer-treatment/). This young and dynamic subgroup regularly hosts international students. The PhD student will also benefit from the scientific environment of the SIGNATHER team (Favre/Sordet), which includes several PhD students. We are located at the CRCT, a new center built in 2014 and representing the research unit of the Oncopole campus, which is a great example in France of symbiosis between research, care and pharmaceutical companies. The CRCT comprises 20 research groups and a cutting edge technological cluster (flow cytometry, imaging, genomics…). The student will benefit from the facilities, equipment and expertise available within the team and at the CRCT, ensuring optimal conditions to carry out the PhD.

We are looking for a highly self-motivated candidate who is curious and enthusiastic about working in a collaborative team, with a strong interest in chromatin, RNA, and genome maintenance. The candidate should hold a M.Sc. degree in Biology, Oncology, Biochemistry, or a related field, and possess wet-lab experience, demonstrated through at least a 6-month internship. Supervision will be provided for all aspects of the work; however, expertise in standard molecular biology techniques, along with a strong interest or expertise in bioinformatics, is particularly welcome. Strong communication skills and the ability to work both autonomously and as part of a team are essential. French is not required if the candidate is fluent in English (writing, speaking, and comprehension).