Project description
Genomic instability in eukaryotic cells: a fitness driver?
Leishmania are protozoan parasites that are transmitted to humans and animals through the bite of infected sandflies, causing a range of diseases. Unlike most eukaryotic cells, Leishmania can increase the expression of specific genes by gene dosage changes through the amplification of entire chromosomes, chromosome regions or individual genes. Funded by the European Research Council, the DECOLeishRN project aims to investigate how Leishmania employ such genome instability to regulate their fitness. Researchers will focus on the molecular mechanisms that can filter toxic from beneficial gene dosage changes, including RNA modifications guided by non-coding RNAs. Given that genomic instability drives cancer development, project findings extend beyond Leishmania.
Objective
Darwinian evolution plays a central yet poorly understood role in human disease. Iterations between genetic mutation and environmental selection drive cancer development, microbial infection and therapeutic failure, thus increasing human mortality. The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in these pathogenic systems are unknown. Here we investigate this important unsolved question in the protozoan parasite Leishmania that causes devastating human infections. In the absence of transcriptional regulation, these early-branching eukaryotes exploit genome instability to regulate expression by gene dosage. Leishmania thus represents an ideal system to investigate how genome instability drives fitness gain in fast evolving, eukaryotic cells, such as observed during cancer development. Synergizing our expertise in genomics, evolution, systems and RNA biology, we have recently made several breakthrough discoveries that link parasite fitness gain to epistatic interactions between co-amplifying genes of small, non-coding RNAs, which program epitranscriptomic and translational regulation. We hypothesize that these genome/RNome interactions generate the phenotypic landscape underlying Leishmania fitness gain. Our proposal investigates this ground-breaking concept through two Specific Aims that (i) combine experimental parasite differentiation and evolution in vitro and in vivo to reveal molecular mechanisms underlying Leishmania predictive adaptation and fitness gain, and (ii) investigate how RNA modification and non-coding RNAs contribute to adaptation by regulating mRNA stability and translational control. Our findings will be highly relevant to other fast growing, eukaryotic systems that rely on genome instability, such as cancer or fungal pathogens.
Fields of science
Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
HORIZON-ERC-SYG - HORIZON ERC Synergy GrantsHost institution
75724 Paris
France