title: Exposure to hycanthone alters chromatin structure around specific gene functions and specific repeats in Schistosoma mansoni.
abstract: Schistosoma mansoni is a parasitic plathyhelminth responsible for intestinal schistosomiasis (or bilharzia), a disease affecting 67 million people worldwide and causing an important economic burden. The schistosomicides hycanthone, and its later proxy oxamniquine, were widely used for treatments in endemic areas during the twentieth century. Recently, the mechanism of action, as well as the genetic origin of a stably and Mendelian inherited resistance for both drugs was elucidated in two strains. However, several observations suggested early on that alternative mechanisms might exist, by which resistance could be induced for these two drugs in sensitive lines of schistosomes. This induced resistance appeared rapidly, within the first generation, but was metastable (not stably inherited). Epigenetic inheritance could explain such a phenomenon and we therefore re-analyzed the historical data with our current knowledge of epigenetics. In addition, we performed new experiments such as ChIP-seq on hycanthone treated worms. We found distinct chromatin structure changes between sensitive worms and induced resistant worms from the same strain. No specific pathway was discovered, but genes in which chromatin structure modifications were observed are mostly associated with transport and catabolism, which makes sense in the context of the elimination of the drug. Specific differences were observed in the repetitive compartment of the genome. We finally describe what types of experiments are needed to understand the complexity of heritability that can be based on genetic and/or epigenetic mechanisms for drug resistance in schistosomes.
authors: Département de Biologie, Université de Perpignan Via Domitia Perpignan, France ; CNRS, UMR 5244, Écologie et Évolution des Interactions (2EI) Perpignan, France.
authors: David
authors: D
authors: Roquis
authors: Département de Biologie, Université de Perpignan Via Domitia Perpignan, France ; CNRS, UMR 5244, Écologie et Évolution des Interactions (2EI) Perpignan, France.
authors: Julie M J
authors: JM
authors: Lepesant
authors: CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, Département de Biologie, Université Lyon 1 Villeurbane, France ; Red de Estudios Moleculares Avanzados, Instituto de Ecología A.C. Xalapa, México.
authors: Emanuel
authors: E
authors: Villafan
authors: Département de Biologie, Université de Perpignan Via Domitia Perpignan, France ; Red de Estudios Moleculares Avanzados, Instituto de Ecología A.C. Xalapa, México.
authors: Jérôme
authors: J
authors: Boissier
authors: CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Évolutive, Département de Biologie, Université Lyon 1 Villeurbane, France ; Département de Biologie, Institut Universitaire de France Paris, France.
authors: Cristina
authors: C
authors: Vieira
authors: Département de Biologie, Université de Perpignan Via Domitia Perpignan, France ; CNRS, UMR 5244, Écologie et Évolution des Interactions (2EI) Perpignan, France.
authors: Céline
authors: C
authors: Cosseau
authors: Département de Biologie, Université de Perpignan Via Domitia Perpignan, France ; CNRS, UMR 5244, Écologie et Évolution des Interactions (2EI) Perpignan, France.
authors: Christoph
authors: C
authors: Grunau
keywords: Schistosoma mansoni; epigenetics; hycanthone; induction; oxamniquine; repetitive sequences; resistance