Genome-wide profiling of cervical RNA-binding proteins identified HPV regulation of RNASEH2A expression by viral E7 and E2F1
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ABSTRACT:
PROVIDER: PRJNA454568 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7091820.fastq.gz | Fastqsanger.gz | |||
| SRR7091821_1.fastq.gz | Fastqsanger.gz | |||
| SRR7091821_2.fastq.gz | Fastqsanger.gz | |||
| SRR7091822_1.fastq.gz | Fastqsanger.gz | |||
| SRR7091822_2.fastq.gz | Fastqsanger.gz |
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Project description:RNA-binding proteins (RBPs) have been shown to control mRNA processing, stability, transport, editing and translation. Application of large-scale quantitative technologies has facilitated genome-wide identification of RBPs and linked their defects to human diseases and carcinogenesis. We have recently conducted transcriptome analysis comparing normal cervical tissues with HPV-positive cervical cancer tissues by using two different RNA-seq platforms. As the results, 614 differentially expressed protein-coding transcripts were identified, which are enriched in cancer related pathways and consist of 95 known RBPs. TaqMan RT-qPCR was used to verify altered expression of 26 genes with a cohort of 72 cervical samples, including 24 normal cervical, 25 CIN 2-3, and 23 cervical cancer tissues. LY6K, FAM83A, CELSR3, ASF1B, IQGAP3, SEMA3F, CLDN10, MSX1, CXCL5, ASRGL1, ELAVL2, GRB7, KHSRP, NOVA1, PTBP1 and RNASEH2A were identified being novel candidates in association with cervical lesion progression and carcinogenesis. We further demonstrated that HPV16 or HPV18 infection leads to altered expression of 8 RBP genes (CDKN2A, ELAVL2, GRB7, HSPB1, KHSRP, NOVA1, PTBP1, and RNASEH2A) in human vaginal and foreskin keratinocytes. While both viral E6 and E7 decrease NOVA1 expression, viral E7 was found to increase the expression of both RNASEH2A and PCNA in an E2F1 dependent manner, two key factors closely associated with the progression of cervical neoplasia. By illustration of the first comprehensive cervical genome expression atlas, we have identified the altered expression of many novel genes due to HPV infection, which could be biomarkers for better diagnosis and treatment of cervical cancer.
2019-04-25 | GSE113942 | GEO
Project description:The study aimed to explore HPV E7-specific pathways in cervical cancer cells.
2024-08-25 | GSE274812 | GEO
Project description:Human papillomavirus (HPV) genome integration into the host genome, blocking E2 expression and leading to overexpression of E6 and E7 viral oncogenes, is considered a major step in cervical cancer development. In high-risk HPVs, E6 and E7 oncogenes are expressed as a bicistronic pre-mRNA, with alternative splicing producing the ultimate mRNAs required for E6 and E7 translation. Given the number of alternative donor and acceptor splicing sites, ten E6/E7 different alternative transcripts might be formed for HPV16 and three for HPV18, although only six isoforms have been previously reported for HPV16. In the present work, we employ high-throughput sequencing of invasive cervical cancer transcriptome (RNA-Seq) to characterize the expression of the HPV genome in 24 invasive cervical cancers associated with HPV16 and HPV18 single infections. Based on high-resolution transcriptional maps, we herein report three viral gene expression patterns which might be associated with the presence of the viral genome in episomal and/or integrated stages. Alternative mRNAs splicing isoforms coding for E6 and E7 oncoproteins were characterized and quantified, and two novel isoforms were identified. Three major isoforms (E6*I, E6*II, and E6+E7) were detected for HPV16 and two for HPV18 (E6*I and E6+E7). Minor transcript isoforms, including the novel ones, were very rare in some tumor samples or were not detected. Our data suggested that minor transcript isoforms of E6/E7 do not play a relevant role in cervical cancer.
2019-08-06 | GSE91065 | GEO
Project description:Aberrant glycosylation is a characteristic of tumor cells. The expression of certain glycan structures has been associated with poor prognosis. In cervical carcinoma has been reported changes in the gene expression level of some glycogenes that has been associated with lymph invasion. Human papilloma virus (HPV) infection is one of the most important factors to develop cervical cancer. HPV oncoproteins E6 and E7 have been implicated in cervical carcinogenesis. The role of these oncoproteins in glycosylation changes has not been reported. To know the effect of these oncoproteins on glycogene expression we realized a partial silencing of oncogenes E6 and E7 in HeLa cells, we made a microarray expression assay and we identified glycogenes that modified its expression. The analysis showed alteration in some glycosylation pathways, like glycosphingolipid, O-glycan mucin-type, and O-glycan non mucin-type glycosylation. Our results suggest that E6 and E7 oncoproteins could modified glycosylation of structures implicated in proliferation, adhesion, and apoptosis.
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Project description:It is well known that high-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and E7 was identified as one of the key initiators in HPV-mediated carcinogenesis. Here we show that lactate dehydrogenase A (LDHA) preferably locates in the nucleus in HPV16-positive cervical tumors due to E7-induced intracellular reactive oxygen species (ROS) accumulation. Surprisingly, nuclear LDHA gains a non-canonical enzyme activity to produce α-hydroxybutyrate and triggers DOT1L (disruptor of telomeric silencing 1-like)-mediated histone H3K79 hypermethylation, resulting in the activation of antioxidant responses and Wnt signaling pathway. Furthermore, HPV16 E7 knocking-out reduces LDHA nuclear translocation and H3K79 tri-methylation in K14-HPV16 transgenic mouse model. HPV16 E7 level is significantly positively correlated with nuclear LDHA and H3K79 tri-methylation in cervical cancer. Collectively, our findings uncover a non-canonical enzyme activity of nuclear LDHA to epigenetically control cellular redox balance and cell proliferation facilitating HPV-induced cervical cancer development.
2018-09-24 | PXD011058 | Pride
Project description:Long noncoding RNAs (lncRNA) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remains unknown. By RNA-seq analyses of 18 clinical samples and validated by RT-qPCR analyses of 72 clinical samples, we provide the first evidence in this report that 194 lncRNAs are differentially regulated by high-risk HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, induced by high-risk HPV infection was carefully analyzed because it is expressed from the same chr 15q26.1 region of FANCI gene encoding an important DNA repair factor. We found a mutual regulation of lnc-FANCI-2 and FANCI in cervical cancer cells and high-risk E6 and mainly E7 for this upregulation independent of p53 and pRb/E2F1. In HPV16-positive CaSki cells, lnc-FANCI-2, primarily in the cytoplasm in ~10 copies per cell, is transcribed from two alternative promoters and polyadenylated at two alternative poly(A) sites. Alternative RNA splicing of lnc-FANCI-2 transcripts leads to produce 14 detectable RNA isoforms. YY1 interacts with viral E7 and transactivates the transcription by binding to two YY1-binding motifs in the lnc-FANCI-2 promoter. Knockdown of either YY1 or E7 expression led to significant reduction of lnc-FANCI-2 expression. The 3’ untranslational region of YY-1 RNA contains a consensus seed match to miR-29a and is sensitive to miR-29a-mediated inhibition of YY1 expression. High-risk HPV infections were found to induce YY1 expression in HPV18-infected HFKs by reduction of host miR-29a expression. Together, our data have provided novel insights into mechanisms of how high-risk HPVs contribute to cervical carcinogenesis.
2021-12-31 | GSE150227 | GEO
Project description:The Octamer-binding transcription factor-4 (Oct4) is upregulated in different malignancies, yet a paradigm for mechanisms of Oct4 post-embryonic re-expression is inadequately understood. In cervical cancer, Oct4 expression is higher in HPV-related than HPV-unrelated cervical cancers and this upregulation correlates with the expression of the E7 oncogene. We have reported that E7 affects the Oct4-transcriptional output and Oct4-related phenotypes in cervical cancer, however, the underlying mechanism remains elusive. Here, we characterize the Oct4-protein interactions in cervical cancer cells and reveal that Methyl-binding proteins (MBD2 and MBD3), are determinants of Oct4 driven transcription. E7 triggers MBD2 downregulation and TET1 upregulation, thereby disrupting the methylation status of the Oct4 gene. This coincides with an increase in the total DNA hydroxymethylation leading to the re-expression of Oct4 in cervical cancer and likely affecting broader transcriptional patterns. Our findings reveal a previously unreported mechanism by which the E7 oncogene can regulate transcription by increasing DNA hydroxymethylation and lowering the barrier to cellular plasticity during carcinogenesis.
2023-12-11 | GSE248367 | GEO
Project description:Human papillomavirus E7 binds Oct4 and regulates its activity in HPV-associated cervical cancers.
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Project description:The life cycle of human papillomaviruses (HPV) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes, however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to down-regulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to down-regulate the expression of several genes involved in keratinocyte differentiation, at least partially by down-regulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus induced carcinogenesis. Primary human foreskin keratinocytes were transduced by retrovirus vectors containing HPV 16 E6, E7, E6/E7 or the control vector LXSN. The global gene expression patterns of transduced keratinocytes were analyzed on Affymetrix microarrays
2014-06-26 | E-GEOD-58841 | biostudies-arrayexpress
Project description:The life cycle of human papillomaviruses (HPV) is strictly linked to the differentiation of their natural host cells. The HPV E6 and E7 oncoproteins can delay the normal differentiation program of keratinocytes, however, the exact mechanisms responsible for this have not yet been identified. The goal of this study was to investigate the effects of HPV16 oncoproteins on the expression of genes involved in keratinocyte differentiation. Primary human keratinocytes transduced by LXSN (control) retroviruses or virus vectors expressing HPV16 E6, E7 or E6/E7 genes were subjected to gene expression profiling. The results of microarray analysis showed that HPV 16 E6 and E7 have the capacity to down-regulate the expression of several genes involved in keratinocyte differentiation. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed to confirm microarray data. To investigate the effects of the HPV oncoproteins on the promoters of selected keratinocyte differentiation genes, luciferase reporter assays were performed. Our results suggest that the HPV 16 E6 and/or E7 oncogenes are able to down-regulate the expression of several genes involved in keratinocyte differentiation, at least partially by down-regulating their promoter activity. This activity of the HPV oncoproteins may have a role in the productive virus life cycle, and also in virus induced carcinogenesis.
2014-06-26 | GSE58841 | GEO