Biology subjects

Brice, C.

Publications and source records attributed to Brice, C..

2 recordsLinked to original sources

bioRxiv2023

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites

Radical cure of Plasmodium vivax malaria must include elimination of quiescent hypnozoite forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials. One-Sentence SummaryDrug repurposing screens reveal several epigenetic inhibitors as active against P. vivax hypnozoites demonstrating that epigenetic pathways play a central role in hypnozoite quiescence.

cell biology↗

bioRxiv2022

The dynamics of adaptation to stress from standing genetic variation and de novo mutations

Adaptation from standing genetic variation is an important process underlying evolution in natural populations but we rarely get the opportunity to observe the dynamics of fitness changes in real time. Here, we used the power of microbial experimental evolution and whole population sequencing to track the phenotypic and genomic changes of genetically diverse yeast populations in environments with different stress levels. We found that populations rapidly and in parallel increased in fitness in stressful environments. The founders genetic diversity was quickly depleted, however, not to the same degree in all populations and environments. Some populations fixed all ancestral variation in < 30 generations while others maintained diversity across hundreds of generations. We also observed parallelism at the gene and pathway level. Specifically, we detected up to seven genes harbouring multiple independent mutations in different populations, and a general enrichment for mutations affecting downstream effectors of the high-osmolarity-glycerol pathway in three out of four environments. Adaptation to the most stressful environment was characterised by the fast evolution of functional haploidy, likely driven by standing genetic variation. Almost 40% of all populations contained aneuploidies (losses or gains of chromosomes) at least once during experimental evolution. Some aneuploidies were maintained for hundreds of generations in parallel in different replicates, suggesting they were adaptive. This work shows that experimental evolution is a great tool to address the interplay between standing variation and the influx of de novo mutations, leading to a better understanding of the demographic and environmental drivers and constraints of a populations capacity to adapt to environmental change.

evolutionary biology↗