Our research aims to investigate the intricate interactions between RNA, TFs and processing factors and how they contribute to cell fate decisions.
Integrating transcription and mRNA processing networks into cell fate decision
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OVERVIEW
Gene expression, the key to cell diversity across all organisms, is governed by transcription factors (TFs) orchestrating intricate gene regulatory networks with precise spatial and developmental timings. Yet, significant challenges persist in elucidating the complexity and dynamics of these networks, as well as in connecting gene expression to cell fate decisions.
Beyond the conventional view that TFs act solely on cis-regulatory DNA elements (promoters, enhancers), we and others have demonstrated that many TFs can bind RNA and modulate mRNA fates. By doing so, TFs regulate a unique layer of molecular diversity through the production of various mRNA isoforms, thus shaping specific proteomes and contributing to cell diversity. Despite its central role in gene networks, the contribution of TF-RNA regulatory functions to cell fate decisions remains largely unexplored. Our research team aims to unravel these unconventional TF-RNA functions and their impact on cell fate changes, both on developmental processes and on dysregulated states observed in diseases.
OUR QUESTIONS
Pre-mRNA processing is a conserved process covering events such as 5’capping, splicing and 3’polyadenylation. It relies on the dynamic assembly of molecular machines, notably the spliceosome, to produce mature mRNAs in precise cell contexts and ensures the production of various mRNA isoforms with great plasticity. Our research goal is to investigate the intricate interactions between RNA, TFs and processing factors, and how they contribute to cell fate decisions.
Specifically, we aim to understand:
1. TF functions on pre-mRNA fate: How do TFs integrate transcription and splicing functions? Do TFs regulate other processing layers?
2. The functional specificity: What drives TF-RNA interaction specificity, and how do these networks coordinate cell fate changes?
3. The conservation of RNA regulation: Are TF-RNA functions universal? Which TFs bind RNA, and how?
OUR APPROACHES
To explore these questions, we focus on the homeodomain (HD) TFs and primarily on the Hox TFs, which are prominent players of cell identity and tissue patterning in animals (see the figure below exemplified with the Drosophila Hox TF Ultrabithorax, our work showed that Ubx regulates alternative splicing). We investigate their role at multiple scales: in vitro, in cell culture and in vivo in Drosophila embryonic muscles, for which the identity and function are regulated at the co-transcriptional and post-transcriptional levels.
Our research is rooted in molecular developmental biology and aims to bridge structural biology and in silico modelling through stimulating collaborations for studying TF-RNA networks from molecules to tissue development. Specifically, we employ biochemistry (RNA-DNA-protein interaction assays), transcriptomics (RNA-seq, RIP-seq), proteomics (BioID, split-BioID coupled with mass spectrometry) and imaging methods (RNA, protein, tissue patterning) combined with in vivo Drosophila genetics (mutants, nanobodies toolkit) for integrative molecular and functional analyses of TF-RNA regulatory functions.
OUR TEAM
