Decoding epistatic genome/RNome interactions in eukaryotic fitness gain using Leishmania parasites as a unique model system

Projektinformationen

DECOLeishRN

ID Finanzhilfevereinbarung: 101071613

DOI

10.3030/101071613

EK-Unterschriftsdatum 13 Dezember 2022

Startdatum 1 Mai 2023

Enddatum 30 April 2029

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 8 620 835,00

EU-Beitrag

€ 8 620 835,00

Koordiniert durch

INSTITUT PASTEUR
France

Periodic Reporting for period 1 - DECOLeishRN (Decoding epistatic genome/RNome interactions in eukaryotic fitness gain using Leishmania parasites as a unique model system)

Berichtszeitraum: 2023-05-01 bis 2024-10-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We will complete this section for the submission of the first progress report by the end of June 2025

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

We will complete this section for the submission of the first progress report by the end of June 2025