Epigenetic Silencing of MicroRNA-126 Promotes Cell Growth in Marek’s Disease

Abstract

During latency, herpesvirus infection results in the establishment of a dormant state in which a restricted set of viral genes are expressed. Together with alterations of the viral genome, several host genes undergo epigenetic silencing during latency. These epigenetic dysregulations of cellular genes might be involved in the development of cancer. In this context, Gallid alphaherpesvirus 2 (GaHV-2), causing Marek’s disease (MD) in susceptible chicken, was shown to impair the expression of several cellular microRNAs (miRNAs). We decided to focus on gga-miR-126, a host miRNA considered a tumor suppressor through signaling pathways controlling cell proliferation. Our objectives were to analyze the cause and the impact of miR-126 silencing during GaHV-2 infection. This cellular miRNA was found to be repressed at crucial steps of the viral infection. In order to determine whether miR-126 low expression level was associated with specific epigenetic signatures, DNA methylation patterns were established in the miR-126 gene promoter. Repression was associated with hypermethylation at a CpG island located in the miR-126 host gene epidermal growth factor like-7 (EGFL-7). A strategy was developed to conditionally overexpress miR-126 and control miRNAs in transformed CD4+ T cells propagated from Marek’s disease (MD) lymphoma. This functional assay showed that miR-126 restoration specifically diminishes cell proliferation. We identified CT10 regulator of kinase (CRK), an adaptor protein dysregulated in several human malignancies, as a candidate target gene. Indeed, CRK protein levels were markedly reduced by the miR-126 restoration.

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“…They were grown at 41°C with 5% of CO 2 . Reactivation was induced by treatment of either 3 mM NaBu or 5 μM 5’azacytidine (Merck) and was verified by the expression of VP5 as previously described ( 51 , 80 , 81 ).…”

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“…Small RNA-seq analysis identified 54 novel miRNAs that were differentially expressed in MDV and control birds ( 64 ). The study demonstrated that miR-126 plays a role in suppressing tumors in Marek’s disease lymphoma ( 65 ). A potential regulatory network of miR-29b-3p and its target gene was identified, which regulates the characteristics of the MD lymphoma transformation ( 66 ).…”

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“…Gennart and Petit et al investigated the role of a cellular micro RNA, miR-126, in MDV infection. Interestingly, miR-126 is known to play key roles in human cancers as well [ 13 ].…”