Database and Statistical Analyses of Transcription Factor Binding Sites in the Non-Coding Control Region of JC Virus

Abstract

JC virus (JCV), as an archetype, establishes a lifelong latent or persistent infection in many healthy individuals. In immunocompromised patients, prototype JCV with variable mutations in the non-coding control region (NCCR) causes progressive multifocal leukoencephalopathy (PML), a severe demyelinating disease. This study was conducted to create a database of NCCR sequences annotated with transcription factor binding sites (TFBSs) and statistically analyze the mutational pattern of the JCV NCCR. JCV NCCRs were extracted from >1000 sequences registered in GenBank, and TFBSs within each NCCR were identified by computer simulation, followed by examination of their prevalence, multiplicity, and location by statistical analyses. In the NCCRs of the prototype JCV, the limited types of TFBSs, which are mainly present in regions D through F of archetype JCV, were significantly reduced. By contrast, modeling count data revealed that several TFBSs located in regions C and E tended to overlap in the prototype NCCRs. Based on data from the BioGPS database, genes encoding transcription factors that bind to these TFBSs were expressed not only in the brain but also in the peripheral sites. The database and NCCR patterns obtained in this study could be a suitable platform for analyzing JCV mutations and pathogenicity.

Rearrangement in the Hypervariable Region of JC Polyomavirus Genomes Isolated from Patient Samples and Impact on Transcription Factor-Binding Sites and Disease Outcomes

“…Given the effectiveness of this approach, we have discovered possible novel TFBS that correlate with JCPyV infection based on location and disease status ( Figure 4 ). This research contributes to a similar study in which computer simulations were utilized to identify TFBSs in the NCCR [ 55 ], leading to new resources for the field and possibly clinicians. Future studies should revisit the outcomes of these TFBS in JCPyV transcription and replication through molecular analyses.…”

“…However, OLIG3 was only significantly more prevalent in sequences isolated from the blood compared to sequences isolated from the urine in block “c” ( p = 0.039, data not shown). There were not significant differences when comparing OLIG3 binding sites in the urine to the CSF and brain but it is important to note that another OLIG gene member, OLIG2 was also revealed in a similar study [ 55 ].…”

“…However, metanalyses to observe the changes in the NCCR in the archetype and PML-type strains as well as tissue location of sequence isolates are very limited. A recent study by Nakamichi et al described the curation of a database with TFBSs in NCCR sequences of archetype and PML-type JCPyV isolates identified through computer simulations [ 55 ]. Our current study provides an extensive bioinformatic approach to validate and uncover TFBS that are influenced by NCCR rearrangements which ultimately enhance viral transcription and cause disease.…”

Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011–2020

“…In individuals with immunocompromised statuses, including those undergoing therapies that affect cellular immunity, JCV can reactivate and replicate in oligodendrocytes, leading to brain demyelination [1,[16][17][18][19]. The JCV responsible for causing PML has a hypervariable mutation with deletions and/or duplications in DNA sequences of the non-coding control region (known as the regulatory or transcription control regions) within the viral genome and is referred to as the prototype [9,16,[20][21][22][23]. PML occurs in the presence of various immunosuppressive conditions, such as HIV infection, hematologic malignancies, and organ transplantation [2,16,24,25].…”