Post-transcriptional regulation of the adaptive immune response and tumorigenesis
Coordinator : M. Diaz Munoz
Development of an effective adaptive immune response is essential for fighting infections and for successful vaccination strategies that protect us against common pathogens. Activation of T and B lymphocytes is central in the adaptive immune response, and their differentiation into memory and plasma cells secures long-term life protection. Understanding the genetic mechanisms controlling lymphocyte development and function is the base of our research.
Genetic information encoded by our genes controls all aspects of the immune response. DNA is finely transcribed into messenger RNA (mRNA) that is then translated into the proteins that modulate immunity. Life of mRNA is complicated. Changes in the nature of its nucleotide sequence as well as changes in mRNA location and stability determine protein abundance and function in immune cells. Timely control of mRNA interaction with RNA binding proteins is essential for mRNA synthesis, editing and translation and for healthy immunity. Our research aims to understand how these RNA binding proteins control fundamental aspects in lymphocyte development and differentiation and how do they prevent T/B- cell tumour transformation. Our research is divided in three main axis.
AXIS 1: Understand how post-transcriptional regulation controls the germinal centre reaction
Germinal centres (GCs) are a hallmark in the fight against pathogens but they are also the source of most non- Hodgkin’s B cell lymphomas. GCs are distinctive anatomical structures formed in our secondary immune organs, such as spleen and lymph nodes, upon infection. They are not only sites for B cell clonal expansion but the places where the antibody repertoire diversifies. In GCs, B cells undergo affinity maturation. This is the process by which mutagenesis of the immunoglobulin Ig genes followed by cell selection generate antibody- producing cells and memory B cells that protect us against recurrent infections. Tight modulation of Ig somatic hypermutation and DNA damage repair is essential for antibody production, and miss- targeted mutations can lead to chromosomal translocation and B cell tumor transformation.
Our research combines the use of transgenics mouse models and next generation sequencing technologies to uncover the role of RNA binding proteins during B cell development, GC reactions and antibody production. We investigate how regulation of mRNA splicing and translation affects lymphocyte metabolism fuelling cell lineage commitment, expansion and differentiation in response to model antigens and infections.
AXIS 2: Post-transcriptional mechanisms for oncogene expression during the genotoxic stress response
Understanding how RNA binding proteins enable Ig- class switch recombination and somatic hypermutation in GC B cells while preserving the genome integrity is fundamental in our research. Mutagenesis and DNA repair are highly regulated processes linked to the cell cycle. The existence of different cell cycle checkpoints (at G1, S and M phases) is essential for evaluation and depletion of GC B cells with extensive mutations. RNA binding proteins plays a fundamental role in these processes as they not only control lymphocyte growth and cell cycle progression but also modulate timely translation of key cell cycle checkpoint proteins and DNA damage regulators like p53.
Our research aims to characterise the molecular mechanisms and signalling pathways that modulate mRNA subcellular location and translation of oncogenes in lymphocytes undergoing active processes of class switch recombination and somatic hypermutation. How RNA-binding proteins contribute to the selection of mutated GC B cells producing high-affinity antibodies while preventing B-cell tumour transformation is a major question yet to be answered.
AXIS 3: Post-transcriptional regulation by MAP Kinases in cancer and immune cells
Post-transcriptional control of protein synthesis has emerged as a central regulator of gene expression in cancer. Most oncogenic pathways lead to translational reprogramming of the genome in order to sustain cancer cell proliferation and affect response to treatment. We previously observed a constitutive activation of MEK, as a consequence of MAP3K8 accumulation in 50% ovarian cancers, independently of KRAS or BRAF mutations. We showed that MAP3K8/MEK exhibits pro-tumorigenic functions and we identified a specific MAP3K8/MEK translational program in cancer cells that could modulate host immune anti-tumor response. We are willing to decipher the causes and consequences of MAP3K8/MEK specific translation in cancer cells and assess how this affects to the immune cells in the TME by analyzing: (1) the role of MAP3K8/MEK activation in cancer and immune cells crosstalk; (2) the molecular mechanism(s) by which constitutive MEK activation induces tumor-associated translational reprogramming; (3) the rational of targeting the mRNA translation machinery in ovarian cancer patients with constitutive MEK activation.
AXIS 4: Development of new tools for transcriptome and translatome analysis in lymphocytes
Understanding the complex regulation of lymphocyte development and differentiation requires deep analysis of the cell genome, transcriptome and translatome. The development of next-generation sequencing (NGS) has led to the definition of networks of mRNA molecules that response similarly to a given stimulus. In these early days, recent technologies are capable of both deciphering the RNA binding properties of hundreds of proteins and identify the set of RNA binding proteins associated to a single transcript, but how this knowledge is translated into regulation of lymphocyte function is under intense scrutiny in our lab.
We now apply NGS methods (iCLIP) to identify physical interactions between RNA binding proteins and their mRNA targets in primary lymphocytes in a global scale. Integration of the protein:RNA interactome with the cell transcriptome and translatome (measured using RiboSeq and Polysome profiling + sequencing) has enable us to uncover key molecular functions of the RNA binding proteins HuR and Tia1 in B lymphocytes. Some of the regulatory functions exerted by these RNA binding proteins over target mRNAs are mediated upon binding to RNA regulatory elements present in the 3’ untranslated region (3’UTR). How HuR and Tia1 binding to 3’UTRs affect mRNA subcellular location, stability and decay are important questions to understand oncogene expression in primary lymphocytes and lymphoma cells.
Our team was established at the CPTP in June 2018. We actively seek to support and recruit young and talented investigators that share our interests in Biomedical Research and Immunology. Informal enquiries will be considered for those wishing to join us. Please send your CV (max. three A4 pages including your scientific contributions) and a cover letter describing your interests by email. Funding options (studentships, fellowships and project-associated work contracts) will be discussed based on candidate’s merits and career expectations.
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APPG ANR 01/04/2021 – 31/09/2024
PLBIO INCA Cancer 01/01/2021 – 31/12/2024
ATIP-Avenir, Plan Cancer, CNRS and INSERM 01/01/2018 – 31/12/2022
Boehringer Ingelheim Fonds 01/09/2020 – 31/08/2023
Ligue contre le cancer 01/10/2021 – 31/12/2022 & 01/10/2020 – 31/12/2021
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