Human papillomaviruses (HPVs) comprise more than 200 types associated with diverse clinical outcomes, ranging from benign lesions caused by low-risk types to cancers driven by high-risk types. These differences are partly driven by variation in the Long Control Region (LCR), a non-coding element that regulates viral gene expression through interactions with viral and host transcription factors (TFs). Although individual TF binding sites have been mapped in a few well-studied HPV types, the broader regulatory differences between high-risk and low-risk HPVs remain poorly defined. Here, we systematically analyzed LCR sequences from 207 HPV types using TF motif scanning and identified 104 TFs with significantly different binding site densities between risk groups. Integration with TCGA transcriptomics data showed that 50 of 69 TF enriched in high-risk types are expressed in HPV-positive head and neck tumors (HNSC) and 53 in HPV-positive cervical tumors (CESC). Analysis of published ChIP-seq datasets further confirmed LCR occupancy for seven of these TFs in HPV18-positive cells. In addition, conservation analysis across clinical isolates of HPV-16 and HPV-18 identified highly conserved TF binding sites overlapping multiple high-risk-enriched TF motifs, suggesting functional constraint on key regulatory elements. Together, these findings reveal distinct TF binding landscapes associated with HPV risk groups and identify candidate host regulators that may contribute to differences in viral transcriptional programs and oncogenic potential across HPV types. 1. Introduction The HPV genome is a double-stranded circular DNA of approximately 8 kb, comprising early genes (E1, E2, E4, E5, E6, E7) and late capsid proteins (L1, L2) under the regulatory control of a non-coding element commonly called the Long Control Region (LCR) [ 5]. The LCR is located between the L1 and E6 open reading frames and spans approximately 400–1000 bp, depending on the HPV type. This region contains the viral origin of replication, the early promoter containing a set of transcription factor (TF) binding sites that control when and where viral genes are expressed. The LCR drives expression of E6 and E7, whose constitutive activity is necessary and sufficient for maintaining the transformed phenotype in HPV-positive cancers [ 6]. LCR-driven transcription, however, operates differently across HPV types. In low-risk types such as HPV-11, the LCR is tightly coupled to epithelial differentiation, with activity suppressed in basal cells and induced only in the differentiating spinous layers [ 7]. Viral integration in high-risk types disrupts the E2 open reading frame, removing its repressive function on the LCR and resulting in overexpression of E6/E7 [ 8]. The LCR also encodes tissue tropism through its enhancer composition, with comparative studies across 14 HPV types showing that genital types, both high- and low-risk, share strong epithelial-specific enhancers, whereas cutaneous types show lower LCR activity [ 9, 10]. A key unresolved question is whether TF binding patterns in the LCR differ systematically between high-risk and low-risk HPV types, and, if so, which regulators underlie these differences. Such differences could reflect adaptation to distinct epithelial niches, differentiation states, persistence strategies, or host transcriptional environments, while also contributing indirectly to differences in oncogenic potential. Although prior studies have documented sequence variation across HPV LCRs and characterized selected TF binding sites in a limited number of genotypes [ 16], a comprehensive, LCR-wide analysis of TF binding enrichment across the full diversity of classified HPV types is lacking. Moreover, the extent to which predicted TF binding sites are conserved across clinical isolates within the same HPV type, an expectation for functionally important elements, has not been systematically evaluated. Here, we compared TF binding sites across the LCRs of 207 HPV types and found that high-risk and low-risk types recruit substantially different sets of host TFs. Of the 104 differentially enriched TFs, 69 showed greater predicted binding density in high-risk LCRs and 35 in low-risk LCRs. A total of 50 of the 69 high-risk TFs were expressed in HPV-positive head and neck squamous cell carcinoma (HNSC) tumors and 53 in HPV-positive cervical cancer (CESC) tumors from the Cancer Genome Atlas (TCGA), suggesting they have the potential to regulate viral transcription in the context of HPV-associated cancer. The remaining TFs include nine composite heterodimer motifs and factors with low or tissue-restricted expression. Seven high-risk TFs were independently confirmed to physically occupy the HPV-18 LCR by ChIP-seq in HPV-18-positive cells. Eight TFs were conserved across ≥90% of both HPV-16 and HPV-18 clinical isolates, pointing to a shared core regulatory program across the two most clinically relevant high-risk types. Finally, we also identified multiple TF sites differentially enriched in the late promoter between high- and low-risk HPV types. Together, these results suggest potential host factors linked to transcriptional differences between HPV types. 2. Materials and Methods 2.1. HPV Genome Collection and LCR Extraction Complete HPV genome sequences for 207 HPV types were obtained from the Papillomavirus Episteme (PaVE) database and NCBI GenBank ( Table S1). Risk classification (27 high-risk; 180 low-risk) was assigned according to the International Agency for Research on Cancer (IARC) Monographs and literature survey. LCR sequences were extracted computationally by identifying the genomic interval between the stop codon of the L1 open reading frame and the start codon of the E6 open reading frame. LCR lengths ranged from 322 to 979 bp (median ≈ 527 bp). For intra-type conservation analysis, 990 complete HPV-16 genomes and 187 complete HPV-18 genomes were downloaded from NCBI GenBank ( Table S2). LCR extraction was performed using the same approach, resulting in 835 HPV-16 LCRs (155 excluded due to incomplete L1/E6 annotations) and 187 HPV-18 LCRs. 2.2. Transcription Factor Binding Site Prediction TF binding sites were identified using the Find Individual Motif Occurrences (FIMO) tool from the MEME Suite [ 17]. Scanning was performed using all 892 human TF position weight matrices from the JASPAR database [ 18] with the following parameters: p-value threshold of 1 × 10 −4, both DNA strands scanned, and 0th-order Markov background model computed from the nucleotide frequencies of all input LCR sequences. To account for the substantial variation in LCR length across HPV types, binding site counts were normalized to binding site density (sites per kilobase), calculated as: Density = (number of binding sites)/(LCR length in kb) This prevents length-dependent bias in which longer LCRs would accumulate more binding sites irrespective of true biological enrichment. To further explore enrichment patterns within a single genus, the analysis was also performed using only alpha-papillomavirus LCR sequences, comparing high-risk and low-risk alpha types directly. Of the 27 types classified as high risk, all but one (HPV-5) belong to alpha-papillomavirus. The motif analysis is provided in Table S3. 2.3. Statistical Analysis of Differential TF Binding Of the 892 TFs scanned, 756 produced at least one binding site hit across all HPV LCRs and were retained for downstream analysis; the remaining 136 TFs had zero hits. For each of these 756 TFs, binding site densities were compared between high-risk ( n = 27) and low-risk ( n = 180) HPV types using the two-sided Mann–Whitney U test. p-values were corrected for multiple testing using the Benjamini–Hochberg procedure to control the false discovery rate (FDR) at 5%. TFs with FDR-adjusted p-values 1 and adjusted p-value 0.5 in each group and projected their positions onto a normalized LCR across 207 HPV types ( and ). Binding sites for individual TFs were detected across many HPV types, indicating that enrichment was not driven by a small subset of genomes with unusually high site density. In high-risk types, enriched TFs were distributed throughout the LCR but showed a higher density toward the 5′ region, including factors such as NACC2, DNTTIP1, RREB1, ZSCAN4, and FOXD3 (). While some TFs exhibited positional variability (e.g., HLF, IRF4, CDX2), most showed consistent positioning across HPV types. A comparable spatial organization was observed in low-risk LCRs ( and Supplementary Figure S1B). Together, these results indicate that both high- and low-risk HPVs share a conserved and spatially organized LCR regulatory architecture. 3.3. High-Risk LCR Regulators Are Expressed in HPV-Positive Tumors To assess the potential functional relevance of HR-enriched TFs, we asked whether these TFs are expressed and active in HPV-positive tumors. We first cross-referenced these TFs with RNA-seq data from TCGA-HNSC (72 HPV-positive, 415 HPV-negative patients) and TCGA-CESC (167 HPV-positive, 8 HPV-negative patients), identifying 50 of 69 HR-enriched TFs as present in HPV-positive HNSC and 53 of 69 in HPV-positive CESC (TPM > 1 in ≥10% of HPV-positive tumors) (). We next examined whether these TFs exhibit HPV-associated expression changes that could alter LCR regulation. Among the 50 TFs in HNSC, 32 were differentially expressed between HPV-positive and HPV-negative tumors (DESeq2, padj 1 (7 upregulated and 3 downregulated), suggesting that an HPV infection may rewire host gene regulatory networks to control LCR transcriptional input. Notably, several TFs associated with transcriptional repression or epithelial differentiation, including HOXC13 [ 31] and the KRAB zinc-finger protein ZSCAN31, were downregulated, consistent with reduced repressive or differentiation-linked constraints at the LCR. In contrast, TFs linked to transcriptional activation or proliferative programs, such as MYCN and ZNF367 [ 32, 33], as well as the chromatin-associated factor SALL3, were upregulated, suggesting increased availability of activator inputs that could enhance LCR activity. A parallel analysis in TCGA-CESC identified 13 of the 53 expressed high-risk-enriched TFs as differentially expressed (|log 2FC| > 1, padj 0.5 sites/kb, FDR 0.5 sites/kb, FDR < 0.05), shown across all HPV types. Each row is one HPV type; Table S1: List of HPV types, accession numbers, and risk used in this manuscript; Table S2: List of accession numbers for HPV-16 and HPV-18 isolates used in this manuscript; Table S3: Motif analysis results presented in this manuscript. Author Contributions D.B. and J.I.F.B. conceived the project and wrote the manuscript. D.B. performed data analysis. All authors have read and agreed to the published version of the manuscript. Funding This work was funded by National Institutes of Health grant R35GM128625. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Data are contained within the article and Supplementary Materials. Code used to perform data analysis is provided as Supplementary file: Supplementary_code.zip. Conflicts of Interest The authors declare no conflict of interest. References Walboomers, J.M.; Jacobs, M.V.; Manos, M.M.; Bosch, F.X.; Kummer, J.A.; Shah, K.V.; Snijders, P.J.; Peto, J.; Meijer, C.J.; Muñoz, N. Human Papillomavirus Is a Necessary Cause of Invasive Cervical Cancer Worldwide. J. Pathol. 1999, 189, 12–19. [ Google Scholar] [ CrossRef] Roman, B.R.; Aragones, A. Epidemiology and Incidence of HPV-Related Cancers of the Head and Neck. J. Surg. Oncol. 2021, 124, 920–922. [ Google Scholar] [ CrossRef] Graham, S.V. The Human Papillomavirus Replication Cycle, and Its Links to Cancer Progression: A Comprehensive Review. 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MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. MDPI and ACS Style Bright, D.; Fuxman Bass, J.I. Comparative Analysis of Transcription Factor Binding Sites in the Long Control Region Across Human Papillomavirus Types. Viruses 2026, 18, 646. https://doi.org/10.3390/v18060646 AMA Style Bright D, Fuxman Bass JI. Comparative Analysis of Transcription Factor Binding Sites in the Long Control Region Across Human Papillomavirus Types. Viruses. 2026; 18(6):646. https://doi.org/10.3390/v18060646 Chicago/Turabian Style Bright, Derrin, and Juan I. Fuxman Bass. 2026. "Comparative Analysis of Transcription Factor Binding Sites in the Long Control Region Across Human Papillomavirus Types" Viruses 18, no. 6: 646. https://doi.org/10.3390/v18060646 APA Style Bright, D., & Fuxman Bass, J. I. (2026). Comparative Analysis of Transcription Factor Binding Sites in the Long Control Region Across Human Papillomavirus Types. Viruse
