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Regulation of Polyomavirus Transcription by Viral and Cellular Factors

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Regulation of Polyomavirus Transcription by Viral and Cellular Factors viruses Review Regulation of Polyomavirus Transcription by Viral and Cellular Factors June F. Yang and Jianxin You * Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-215-573-6781 Received: 21 August 2020; Accepted: 22 September 2020; Published: 24 September 2020 Abstract: Polyomavirus infection is widespread in the human population. This family of viruses normally maintains latent infection within the host cell but can cause a range of human pathologies, especially in immunocompromised individuals. Among several known pathogenic human polyomaviruses, JC polyomavirus (JCPyV) has the potential to cause the demyelinating disease progressive multifocal leukoencephalopathy (PML); BK polyomavirus (BKPyV) can cause nephropathy in kidney transplant recipients, and Merkel cell polyomavirus (MCPyV) is associated with a highly aggressive form of skin cancer, Merkel cell carcinoma (MCC). While the mechanisms by which these viruses give rise to the relevant diseases are not well understood, it is clear that the control of gene expression in each polyomavirus plays an important role in determining the infectious tropism of the virus as well as their potential to promote disease progression. In this review, we discuss the mechanisms governing the transcriptional regulation of these pathogenic human polyomaviruses in addition to the best-studied simian vacuolating virus 40 (SV40). We highlight the roles of viral cis-acting DNA elements, encoded proteins and miRNAs that control the viral gene expression. We will also underline the cellular transcription factors and epigenetic modifications that regulate the gene expression of these viruses. Keywords: polyomavirus; transcription; tropism; cis-acting regulatory elements; cell type-specific transcription factors; epigenetic modifications 1. Introduction Polyomaviruses are a family of nonenveloped small circular dsDNA viruses that infect a variety of host species, including humans and other primates. The human polyomaviruses JCPyV, BKPyV, and MCPyV are known to widely infect the human population, but in rare cases, cause severe diseases [1]. In immunosuppressed individuals, JCPyV can reactivate from latency to cause the demyelinating disease PML, a fatal pathology of the central nervous system (CNS) [2]. BKPyV is shed in the urine of immunocompetent individuals but in states of immunosuppression is associated with nephropathy, a leading cause of kidney transplant failure [3]. In immunocompromised individuals and the elderly, MCPyV integrates into its host cell genome to cause Merkel cell carcinoma (MCC), a highly aggressive and fatal skin cancer with a steadily increasing incidence rate in recent years [1,4]. For these viruses, the specific molecular events causing asymptomatic viral infection to progress into the relevant diseases have yet to be elucidated. Members of the polyomaviridae family share the same general genomic structure (Figure1, depicting MCPyV as an example). The circular genome is divided into the early and late regions, based on the temporal regulation of how these genes are expressed during infection. The early gene locus encodes the tumor (T) antigens, which initiate viral replication and interact with host factors to manipulate the cell cycle. The late gene locus encodes the Viral Proteins (VPs), which are structural Viruses 2020, 12, 1072; doi:10.3390/v12101072 www.mdpi.com/journal/viruses Viruses 2020, 12, 1072 2 of 18 Viruses 2020, 12, x FOR PEER REVIEW 2 of 18 proteinsproteins needed needed to toassemble assemble the the viral viral capsid. TheThe latelate regions regions of of SV40, SV40, JCPyV, JCPyV, and and BKPyV BKPyV also also encode encodea small a small regulatory regulatory protein protein called called agnoprotein agnoprotein [5]. Transcription[5]. Transcription of the of earlythe early and and late late genes genes occurs occursin a in bidirectional a bidirectional manner manner from from the the noncoding noncoding regulatory regulatory region region (NCRR), (NCRR), also also referred referred to to as as the the noncodingnoncoding control region (NCCR), (NCCR), which which contains contains ciscis-regulatory-regulatory elements elements as as well well as asthe the origin origin of of replicationreplication [4,6] [4 (Figure,6] (Figure 1).1 ). FigureFigure 1. Genome 1. Genome organization organization of ofMerkel Merkel cell cell polyomaviruspolyomavirus (MCPyV). (MCPyV). The The MCPyV MCPyV genome genome is divided is dividedinto theinto early the early (right) (right) and late and (left) late region(left) region by the by noncoding the noncoding regulatory regulatory region region (NCRR) (NCRR) [4]. The [4]. early Theregion early region encodes encodes large tumor large antigen tumor (LT),antigen small (LT), tumor small antigen tumor (sT), antigen and the(sT), 57 and kT antigenthe 57 kT by antigen differential by differentialsplicing, as wellsplicing, as the as protein well as encoded the protein by an enco Alternateded by frame an Alternate of the LT frame open of reading the LT frame open (ALTO) reading [7 ,8]. frameThe (ALTO) late region [7,8]. encodes The late the region capsid encodes proteins, theVP1 capsid and proteins, VP2. Gene VP1 expression and VP2. isGene regulated expression by NCRR, is regulatedwhich containsby NCRR, the which origin contains of replication the origin (ori) andof re theplication promoters (ori) that and drive the promoters early and latethat gene drive expression. early andMCPyV late gene also expression. encodes a microRNAMCPyV also (MCV-miR-M1), encodes a microRNA which targets (MCV-miR-M1), early transcripts which [9 ].targets early transcripts [9]. The polyomaviruses typically have a very narrow host range and a restricted cell type tropism; inThe particular, polyomaviruses the in vitro typicallytropism have of a JCPyV very narrow is restricted host range to human and a glialrestricted cells, cell while type MCPyV tropism; only in particular,productively the infects in vitro human tropism dermal of JCPyV fibroblasts is restricted (HDFs) to [1 human,10,11]. glial Polyomavirus cells, while gene MCPyV transcription only productivelyappears to infects be a key human determinant dermal forfibroblasts their viral (HDFs) tropism [1,10,11]. as well Polyomavirus as their pathogenic gene potentialtranscription [10,12 ], appearshighlighting to be a key the importancedeterminant of for studying their viral the tropism underlying as well mechanisms. as their pathogenic In this review, potential we discuss[10,12], the highlightingcurrent understanding the importance of of how studying JCPyV, the BKPyV, under MCPyV,lying mechanisms. as well as theIn this well-studied review, we SV40, discuss transcribe the currentthe viral understanding genes to contribute of how JCPyV, to the BKPyV, viral life MCPyV, cycle and as associatedwell as the humanwell-studied diseases. SV40, We transcribe will review the howviral the genes viral tocis contribute-acting regulatory to the viral elements, life cycle virus-encoded and associated proteins human and diseases. miRNAs, We cell will type-specific review howtranscription the viral cis-acting factors, regulatory and epigenetic elements, modifications virus-encoded regulate proteins viral transcription. and miRNAs, cell type-specific transcription factors, and epigenetic modifications regulate viral transcription. 2. Viral Noncoding Regulatory Region 2. Viral ForNoncoding polyomaviruses, Regulatory the Region transcriptional control exerted by cis-acting regulatory elements such as promoters, enhancers, and silencers is an important factor contributing to the virus’ ability to For polyomaviruses, the transcriptional control exerted by cis-acting regulatory elements such complete its life cycle in the host cell [12–15]. This is especially true for MCPyV and JCPyV, each of as promoters, enhancers, and silencers is an important factor contributing to the virus’ ability to which maintain a highly restrictive in vitro host range limited to human and chimpanzee dermal complete its life cycle in the host cell [12–15]. This is especially true for MCPyV and JCPyV, each of fibroblasts and human glial cells, respectively [11,13]. The NCRR region of the primate polyomaviruses which maintain a highly restrictive in vitro host range limited to human and chimpanzee dermal contains a core origin region that includes a poly A/T tract essential for the initial unwinding of fibroblasts and human glial cells, respectively [11,13]. The NCRR region of the primate polyomaviruses contains a core origin region that includes a poly A/T tract essential for the initial unwinding of the viral DNA during replication [16,17] (Figure 2). Overall, however, the sequence Viruses 2020, 12, 1072 3 of 18 Viruses 2020, 12, x FOR PEER REVIEW 3 of 18 the viral DNA during replication [16,17] (Figure2). Overall, however, the sequence and structure andof the structure NCRR areof highlythe NCRR varied are among highly the varied different among polyomaviruses the different (Figurepolyomaviruses2A). Specific (Figure strains 2A). of Specificeach polyomavirus strains of each also polyomavir contain rearrangementsus also contain of rearrangements the NCRR structure, of the leading NCRR tostructure, the categorization leading to theof certain categorization polyomavirus of certain strains polyomavirus as “archetypal” strain ors as “prototypical” “archetypal” based or “prototypical” on the presence based
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