Enhancer-promoter activation by the Kaposi sarcoma-associated herpesvirus episome maintenance protein LANA
Xiang Ye,
Lindsey N. Guerin,
Ziche Chen,
Suba Rajendren,
William Dunker,
Yang Zhao,
Ruilin Zhang,
Emily Hodges,
John Karijolich
Affiliations
Xiang Ye
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Lindsey N. Guerin
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Ziche Chen
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Suba Rajendren
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
William Dunker
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Yang Zhao
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Ruilin Zhang
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Emily Hodges
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
John Karijolich
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN 37232, USA; Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN 37232, USA; Vanderbilt Center for Immunobiology, Nashville, TN 37232, USA; Corresponding author
Summary: Higher-order genome structure influences the transcriptional regulation of cellular genes through the juxtaposition of regulatory elements, such as enhancers, close to promoters of target genes. While enhancer activation has emerged as an important facet of Kaposi sarcoma-associated herpesvirus (KSHV) biology, the mechanisms controlling enhancer-target gene expression remain obscure. Here, we discover that the KSHV genome tethering protein latency-associated nuclear antigen (LANA) potentiates enhancer-target gene expression in primary effusion lymphoma (PEL), a highly aggressive B cell lymphoma causally associated with KSHV. Genome-wide analyses demonstrate increased levels of enhancer RNA transcription as well as activating chromatin marks at LANA-bound enhancers. 3D genome conformation analyses identified genes critical for latency and tumorigenesis as targets of LANA-occupied enhancers, and LANA depletion results in their downregulation. These findings reveal a mechanism in enhancer-gene coordination and describe a role through which the main KSHV tethering protein regulates essential gene expression in PEL.
