Défense de thèse de doctorat en sciences, par Isabelle Gennart

Study of the epigenetic silencing of a host microRNA in Marek’s disease

Jury

Sylvie LAURENT (INRA), Carine VAN LINT (ULB), Benjamin DEWALS (ULg), Nicolas GILLET (UNamur), président, Benjamin LE CALVE (UNamur), Benoît MUYLKENS (UNamur), promoteur

Résumé

The Gallid herpesvirus-2 (GaHV-2) naturally infects chicken and is responsible of Marek’s disease (MD). MD is a robust model for studying virus-induced tumour formation. During the infection, GaHV-2 modulates viral and cellular gene expression and triggers transformation of latently infected cells. The importance of viral and cellular microRNAs (miR) in host-pathogen interactions has been identified recently and additional research is needed to better understand their roles. This study focuses on an intragenic host miR, gga-miR-126, mediating proper angiogenesis. This miR has been reported to impair cancer progression through signaling pathways that control cell proliferation and survival. The main part of this work determined miR-126 expression level at the key steps of GaHV-2 infection (in vitro and in vivo) and looked out for epigenetic modifications involved in the control of its expression. The cellular miRNA was found to be repressed during the viral-induced oncogenesis phase. In order to determine whether miR-126 low expression level was associated with species epigenetic signatures and with peculiar transcription profiles, DNA methylation patterns and transcriptional isoforms were established. Repression was found to be associated with hypermethylation at a CpG island located in the miR-126 host gene (egfl-7). Moreover, transcriptional isoforms analysis showed the existence of alternative promoters during chicken development. This analysis also permitted revealing the existence of two main initiation sites associated each with a CpG islands. Since miR-126 repression is likely to play a pivotal role in altering gene expression patterns during cell transformation, we investigated the impact of miR-126 restoration. A strategy was developed to overexpress miR-126 and control miRNAs in transformed CD4+ T cells propagated from MD lymphoma. To this end, a conditional expression system was developed to counteract miR-126 shutdown. The preliminary functional analysis showed that miR-126 inhibition might participate to the cancerous process induced by GaHV-2 by supporting cell proliferation.

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