Global CpG DNA Methylation Footprint in Kaposi's Sarcoma.

Guy Journo,Meir Shamay,David Dias-Polak,Yonatan Eran,Reuven Bergman,Anuj Ahuja

doi:10.3389/fcimb.2021.666143

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV), also familiar as human herpesvirus 8 (HHV-8), is one of the well-known human cancer-causing viruses. KSHV was originally discovered by its association with Kaposi’s sarcoma (KS), a common AIDS-related neoplasia. Additionally, KSHV is associated with two B-lymphocyte disorders; primary effusion lymphoma (PEL) and Multicentric Castlemans Disease (MCD). DNA methylation is an epigenetic modification that is essential for a properly functioning human genome through its roles in chromatin structure maintenance, chromosome stability and transcription regulation. Genomic studies show that expressed promoters tend to be un-methylated whereas methylated promoters tend to be inactive. We have previously revealed the global methylation footprint in PEL cells and found that many cellular gene promoters become differentially methylated and hence differentially expressed in KSHV chronically infected PEL cell lines. Here we present the cellular CpG DNA methylation footprint in KS, the most common malignancy associated with KSHV. We performed MethylationEPIC BeadChip to compare the global methylation status in normal skin compared to KS biopsies, and revealed dramatic global methylation alterations occurring in KS. Many of these changes were attributed to hyper-methylation of promoters and enhancers that regulate genes associated with abnormal skin morphology, a well-known hallmark of KS development. We observed six-fold increase in hypo-methylated CpGs between early stage of KS (plaque) and the more progressed stage (nodule). These observations suggest that hyper-methylation takes place early in KS while hypo-methylation is a later process that is more significant in nodule. Our findings add another layer to the understanding of the relationship between epigenetic changes caused by KSHV infection and tumorigenesis.

Highlights

Kaposi’s sarcoma-associated herpesvirus (KSHV), familiar as human herpesvirus 8 (HHV- 8), belongs to the g-herpesvirus family and is one of the well-known human cancer-causing viruses (Chang et al, 1994; Purushothaman et al, 2016)
KSHV is associated with two B-lymphocyte disorders; primary effusion lymphoma (PEL) and Multicentric Castlemans Disease (MCD), which are characterized by proliferation of B-cells in body cavities and lymph nodes, respectively (Parravicini et al, 2000; Henke-Gendo and Schulz, 2004)
We have previously revealed the global methylation footprint in PEL cells and found that many cellular gene promoters become differentially methylated and differentially expressed in KSHV chronically infected PEL cell lines (Journo et al, 2018)

Summary

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV), familiar as human herpesvirus 8 (HHV- 8), belongs to the g-herpesvirus family and is one of the well-known human cancer-causing viruses (Chang et al, 1994; Purushothaman et al, 2016). KSHV was originally discovered by its association with Kaposi’s sarcoma (KS) (Chang et al, 1994), a common AIDS-related neoplasia of endothelial/. Similar to other herpes viruses, KSHV infection can be characterized as lytic or latent. Virions are assembled and released from the cell This process requires DNA synthesis together with expression of virion structural protein genes and results in death of the infected cell. Latent infection is characterized by the persistence of the viral genome as a covalently closed circular episome DNA with very limited viral gene expression. In recent years there have been several advancements in our understanding of KS including promising targeted therapeutic agents, but despite these advances, KS still remains the most prevalent malignancy among patients with AIDS and continues to plague patients with drug-related or transplant-associated immunosuppression

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