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The Human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter

Hasan, Uzma A., Zannetti, Claudia, Parroche, Peggy, Goutagny, Nadège, Malfroy, Marine, Roblot, Guillaume, Carreira, Christine, Hussain, Ishraq, Müller, Martin, Taylor-Papadimitriou, Joyce, Picard, Didier, Sylla, Bakary S., Trinchieri, Giorgio, Medzhitov, Ruslan, Tommasino, Massimo·2013·Journal of Experimental Medicine
DOI 10.1084/jem.20122394PMC PMC3698525
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Abstract

Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-κBp50–p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-κB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor.

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Crossref · 10.1084/jem.20122394

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Figures

Figure 1. TLR9 expression is suppressed 24 h after infection by native 16QsV. (A, left) C33A cells were not treated (NT) or treated for 8 or 24 h with TNF, PV, 16QsV (at 107 viral concentrations genome equivalents), 16UV (rendered replication incompetent using UV), CpG 2006, GpC 2006, or infected with HSV-2. TLR9 mRNA levels were determined by qPCR. Shown are data from four independent experiments performed in triplicate. Error bars indicate SEM. (A, right) TLR9 protein was examined by immunoblotting in C33A cells. Cells were harvested after 24 h treatment with PV, TNF, 16UV, 16QsV CpG 2006, and GpC control. (B) C33A cells were treated with increasing viral concentrations genome equivalents (v.g.e.; as measured by qPCR on the viral DNA of infected cells) of 16QsV for 8 or 24 h). E1, E7 (left and middle), and TLR9 mRNA levels (right) were determined for their relative expression by qPCR. Shown are data from five independent experiments performed in duplicate with ***, P < 0.0001, based on an unpaired Student’s t test. (C) C33A cells were infected as indicated for 24 h. siRNA against HPV16E6E7 was transfected 24 h after stimulation and TLR9 mRNA levels were determined by qPCR. Shown are data from four independent experiments performed in triplicate and error bars indicate SEM with ***, P < 0.0001, based on an unpaired Student’s t test. (D) C33A cells were transfected with the TLR9 luciferase promoter and, 24 h later, treated with 16 or control PV. siRNA against HPV16E6E7 was transfected 24 h after infection and TLR9 luciferase levels were measured 18 h later. Shown are data from four independent experiments performed in triplicate, and error bars indicate SEM with ***, P < 0.0001, based on an unpaired Student’s t test. (E, left) HK transduced with the pLXSN vector control or HPV16E7 were stimulated for 24 h with TLR9 agonist CpG ODN 2216 (type A IFN inducer) and the IFN bioassay was performed. (E, middle) C33A cells were unstimulated or infected with 16QsV or PV for 36 h, and cells were washed and then treated with CpG 2216 for 24 h. Supernatants were collected and the type I IFN bioassay was performed. (E, right) C33A cells were stimulated with GpC or CpG 2216 for 24 h and then infected with 16QsV for 36 h. Supernatants were harvested and treated with anti-IFNR or IgG control and the type I IFN bioassay was performed as described. (F) C33A cells were unstimulated and infected with 16QsV for 36 h + CpG 2216 stimulation for 24 h or vice versa ± anti-IFNR or IgG control. Cells were harvested for RNA extraction and qRT-PCR was performed for E1 (left) or E7 (right) relative gene expression. Shown are data from four independent experiments performed in triplicate, and error bars indicate SEM with ***, P < 0.0001, based on an unpaired Student’s t test. (G) HK cells were transfected for a total of 48 h with shTLR9 and shControl (scramble sequence). 20 h after transfection, HK cells were infected for 24 h with 16QsV at a viral load of 107 v.g.e. Viral load was measured by qPCR using E6- and E7-specific primers. HPV16 E6 and E7 transcripts were also measured by qPCR and TLR9 transcripts were assessed by qPCR after 24 h transfection with shRNA. Data are representative of six independent experiments performed in triplicate. Shown are the mean ± SEM with ***, P < 0.0001, based on an unpaired Student’s t test.
Figure 1. TLR9 expression is suppressed 24 h after infection by native 16QsV. (A, left) C33A cells were not treated (NT) or treated for 8 or 24 h with TNF, PV, 16QsV (at 107 viral concentrations genome equivalents), 16UV (rendered replication incompetent using UV), CpG 2006, GpC 2006, or infected with HSV-2. TLR9 mRNA levels were determined by qPCR. Shown are data from four independent experiments performed in triplicate. Error bars indicate SEM. (A, right) TLR9 protein was examined by immunoblotting in C33A cells. Cells were harvested after 24 h treatment with PV, TNF, 16UV, 16QsV CpG 2006, and GpC control. (B) C33A cells were treated with increasing viral concentrations genome equivalents (v.g.e.; as measured by qPCR on the viral DNA of infected cells) of 16QsV for 8 or 24 h). E1, E7 (left and middle), and TLR9 mRNA levels (right) were determined for their relative expression by qPCR. Shown are data from five independent experiments performed in duplicate with ***, P < 0.0001, based on an unpaired Student’s t test. (C) C33A cells were infected as indicated for 24 h. siRNA against HPV16E6E7 was transfected 24 h after stimulation and TLR9 mRNA levels were determined by qPCR. Shown are data from four independent experiments performed in triplicate and error bars indicate SEM with ***, P < 0.0001, based on an unpaired Student’s t test. (D) C33A cells were transfected with the TLR9 luciferase promoter and, 24 h later, treated with 16 or control PV. siRNA against HPV16E6E7 was transfected 24 h after infection and TLR9 luciferase levels were measured 18 h later. Shown are data from four independent experiments performed in triplicate, and error bars indicate SEM with ***, P < 0.0001, based on an unpaired Student’s t test. (E, left) HK transduced with the pLXSN vector control or HPV16E7 were stimulated for 24 h with TLR9 agonist CpG ODN 2216 (type A IFN inducer) and the IFN bioassay was performed. (E, middle) C33A cells were unstimulated or infected with 16QsV or PV for 36 h, and cells were washed and then treated with CpG 2216 for 24 h. Supernatants were collected and the type I IFN bioassay was performed. (E, right) C33A cells were stimulated with GpC or CpG 2216 for 24 h and then infected with 16QsV for 36 h. Supernatants were harvested and treated with anti-IFNR or IgG control and the type I IFN bioassay was performed as described. (F) C33A cells were unstimulated and infected with 16QsV for 36 h + CpG 2216 stimulation for 24 h or vice versa ± anti-IFNR or IgG control. Cells were harvested for RNA extraction and qRT-PCR was performed for E1 (left) or E7 (right) relative gene expression. Shown are data from four independent experiments performed in triplicate, and error bars indicate SEM with ***, P < 0.0001, based on an unpaired Student’s t test. (G) HK cells were transfected for a total of 48 h with shTLR9 and shControl (scramble sequence). 20 h after transfection, HK cells were infected for 24 h with 16QsV at a viral load of 107 v.g.e. Viral load was measured by qPCR using E6- and E7-specific primers. HPV16 E6 and E7 transcripts were also measured by qPCR and TLR9 transcripts were assessed by qPCR after 24 h transfection with shRNA. Data are representative of six independent experiments performed in triplicate. Shown are the mean ± SEM with ***, P < 0.0001, based on an unpaired Student’s t test.CC BY-NC-SA · PubMed Central
Figure 2. HPV16E7 activates the NF-κB pathway that leads to the suppression of TLR9. (A, top) C33A cells were treated with siRNA for IKKα or β for 16 h, and then transfected with TLR9 luciferase promoter. After 24 h, cells were exposed to the indicated treatments and harvested 24 h later to measure activity (left). IKKα or β levels as determined by immunoblotting (right) were analyzed. (A, bottom) C33A cells were treated with siRNA for IKKα or β for 24 h and TLR9 mRNA levels were measured by qPCR. Shown are data from six independent experiments performed in triplicate and error bars indicate SEM. (B) SiHa (HPV16+), HeLa (HPV18+), CaSki (HPV16+), and C33A control cells were treated with the IKKβ inhibitor Bay11. At the indicated times, mRNA and protein expression of TLR9 as well as protein levels of IκBα was determined by immunoblotting. Shown are data from seven independent experiments performed in triplicate and error bars indicate SEM. RE, mRNA relative expression. (C) SiHa cells were treated with Bay11 for the indicated time and immunofluorescence was performed to determine NF-κBp65 cellular localization (red) and TLR9 expression (green). Nuclear staining was controlled using DAPI. Shown are data from one out of four examined fields and one out of three independent experiments. Bars, 10 µm. (D) Human female primary keratinocytes (HK) were transduced with the indicated retroviruses and transfected with the NF-κB reporter gene construct. At 48 h after transfection, luciferase activity was determined. Data are from one assay representative of seven independent experiments; shown are mean ± SEM from triplicate values in three. (E) EMSA was performed on HPV16E7-transduced HK using the NF-κB EMSA kit (Panomics) according to the manufacturer’s instructions. For the supershift analyses, nuclear extracts were incubated with NF-κBp50 or p65 or IgG control. The arrow indicates NF-κB complexes, and the asterisk indicates a supershift. Shown are data from one out of four independent experiments that gave identical results. (F, left) HKs were retrovirally transduced with HPV16E7, empty vector (pLXSN), or HPV16E7ΔN-IκBα and were harvested at the doubling population 7 and stained by immunofluorescence for TLR9 and NF-κBp65. Either Alexa Fluor 488 nm (green) or 594 nm (red) was used as secondary antibodies. Nuclear staining was controlled using DAPI. Shown are data from one out of six examined fields and one out of three independent experiments. Bars, 10 µm. (F, right) Western blot for ΔN-IκBα (marked with an arrow), E7, and β-actin. Shown are data from one out of five independent experiments that gave identical results.
Figure 2. HPV16E7 activates the NF-κB pathway that leads to the suppression of TLR9. (A, top) C33A cells were treated with siRNA for IKKα or β for 16 h, and then transfected with TLR9 luciferase promoter. After 24 h, cells were exposed to the indicated treatments and harvested 24 h later to measure activity (left). IKKα or β levels as determined by immunoblotting (right) were analyzed. (A, bottom) C33A cells were treated with siRNA for IKKα or β for 24 h and TLR9 mRNA levels were measured by qPCR. Shown are data from six independent experiments performed in triplicate and error bars indicate SEM. (B) SiHa (HPV16+), HeLa (HPV18+), CaSki (HPV16+), and C33A control cells were treated with the IKKβ inhibitor Bay11. At the indicated times, mRNA and protein expression of TLR9 as well as protein levels of IκBα was determined by immunoblotting. Shown are data from seven independent experiments performed in triplicate and error bars indicate SEM. RE, mRNA relative expression. (C) SiHa cells were treated with Bay11 for the indicated time and immunofluorescence was performed to determine NF-κBp65 cellular localization (red) and TLR9 expression (green). Nuclear staining was controlled using DAPI. Shown are data from one out of four examined fields and one out of three independent experiments. Bars, 10 µm. (D) Human female primary keratinocytes (HK) were transduced with the indicated retroviruses and transfected with the NF-κB reporter gene construct. At 48 h after transfection, luciferase activity was determined. Data are from one assay representative of seven independent experiments; shown are mean ± SEM from triplicate values in three. (E) EMSA was performed on HPV16E7-transduced HK using the NF-κB EMSA kit (Panomics) according to the manufacturer’s instructions. For the supershift analyses, nuclear extracts were incubated with NF-κBp50 or p65 or IgG control. The arrow indicates NF-κB complexes, and the asterisk indicates a supershift. Shown are data from one out of four independent experiments that gave identical results. (F, left) HKs were retrovirally transduced with HPV16E7, empty vector (pLXSN), or HPV16E7ΔN-IκBα and were harvested at the doubling population 7 and stained by immunofluorescence for TLR9 and NF-κBp65. Either Alexa Fluor 488 nm (green) or 594 nm (red) was used as secondary antibodies. Nuclear staining was controlled using DAPI. Shown are data from one out of six examined fields and one out of three independent experiments. Bars, 10 µm. (F, right) Western blot for ΔN-IκBα (marked with an arrow), E7, and β-actin. Shown are data from one out of five independent experiments that gave identical results.CC BY-NC-SA · PubMed Central
Figure 3. TLR9 promoter regulation by HPV16E7 depends on the locality of the NF-κB complex at a specific cis site. (A) Predicted NF-κB binding sites (A, B, C, and D) in the TLR9 promoter. Sequence mutations were made at site A, B, C, and D to inactivate the binding sites. Top sequences are the native form; bottom sequences indicate the mutations made. (B) HKs were transduced with HPV16E7 or empty vector. Transduced cells were then transfected with TLR9 promoter luciferase expression vectors containing either a wt promoter sequence or sequences with the mutation in the A, B, C, or D site indicated in A. 40 h after transfection, luciferase activity was measured. Shown are data from six independent experiments performed in triplicate and error bars indicate SEM. (C) The binding of NF-κB complexes to the TLR9 promoter in HK was determined by ChIP and ReChIP assays. Sheared chromatin from HK transduced with HPV16E7 or stimulated with TNF or CpG 2006 (4 and 24 h) was immunoprecipitated with antibodies to NF-κBp50 or p65. Site B on the TLR9 promoter was amplified by qPCR to determine the specific binding of transcription factors bound to DNA. Immunoprecipitated DNA and input DNA was amplified with gene-specific and β-globin (Hbb) primers by qPCR, using input DNA to generate a standard curve. ChIP data are represented as % input (gene-specific)/% input(β-globin) = occupancy site B. Shown are data from six independent experiments performed in triplicate and error bars indicate SEM. (D) Re-ChIP analysis was performed for p50–p65 NF-κB complexes using C33A cells first infected with 16QsV for 36 h. Cells were then transfected with siRNA for HPV16E7 and harvested 24 h later. Shown are data from five independent experiments performed in triplicate and error bars indicate SEM. (E) E7 does not bind to the NF-kB cis element site B. ChIP was performed using human epithelial cells transfected with pbabe HA, pbabe HPV16E7-HA, or stimulated with CpG (4 h) or TNF (8 h). ChIP was performed using HA, NF-κBp50 or p65, or an IgG control antibody to examine occupancy of site B. Shown are data from six independent experiments performed in triplicate, and error bars indicate SEM. Shown is an immunoblot to control the ChIP for HA-E7.
Figure 3. TLR9 promoter regulation by HPV16E7 depends on the locality of the NF-κB complex at a specific cis site. (A) Predicted NF-κB binding sites (A, B, C, and D) in the TLR9 promoter. Sequence mutations were made at site A, B, C, and D to inactivate the binding sites. Top sequences are the native form; bottom sequences indicate the mutations made. (B) HKs were transduced with HPV16E7 or empty vector. Transduced cells were then transfected with TLR9 promoter luciferase expression vectors containing either a wt promoter sequence or sequences with the mutation in the A, B, C, or D site indicated in A. 40 h after transfection, luciferase activity was measured. Shown are data from six independent experiments performed in triplicate and error bars indicate SEM. (C) The binding of NF-κB complexes to the TLR9 promoter in HK was determined by ChIP and ReChIP assays. Sheared chromatin from HK transduced with HPV16E7 or stimulated with TNF or CpG 2006 (4 and 24 h) was immunoprecipitated with antibodies to NF-κBp50 or p65. Site B on the TLR9 promoter was amplified by qPCR to determine the specific binding of transcription factors bound to DNA. Immunoprecipitated DNA and input DNA was amplified with gene-specific and β-globin (Hbb) primers by qPCR, using input DNA to generate a standard curve. ChIP data are represented as % input (gene-specific)/% input(β-globin) = occupancy site B. Shown are data from six independent experiments performed in triplicate and error bars indicate SEM. (D) Re-ChIP analysis was performed for p50–p65 NF-κB complexes using C33A cells first infected with 16QsV for 36 h. Cells were then transfected with siRNA for HPV16E7 and harvested 24 h later. Shown are data from five independent experiments performed in triplicate and error bars indicate SEM. (E) E7 does not bind to the NF-kB cis element site B. ChIP was performed using human epithelial cells transfected with pbabe HA, pbabe HPV16E7-HA, or stimulated with CpG (4 h) or TNF (8 h). ChIP was performed using HA, NF-κBp50 or p65, or an IgG control antibody to examine occupancy of site B. Shown are data from six independent experiments performed in triplicate, and error bars indicate SEM. Shown is an immunoblot to control the ChIP for HA-E7.CC BY-NC-SA · PubMed Central
Figure 4. The negative regulatory effect of HPV16 on the TLR9 promoter requires NF-κB and ERα binding to site B flanking sequences in human epithelial cells and HK. (A, top) Diagram illustrates the minimal B site promoter. (A, bottom) Human epithelial cervical cells were transfected with the NF-κB luciferase consensus site, the B minimal promoter or the control vector pTAL. 24 h after transfection 16QsV, control PV (native), CpG 2006, or TNF were added. Cells were harvested and luciferase activity was measured after 24 h. (B, top) Diagram depicting constructs including a 200 bp sequence of the TLR9 promoter containing the NF-κB cis element on site B WT (B200) or mutated (Bm). (B, bottom) C33A cells were transfected with B200 or B200m. 24 h after transfection, 16QsV or TNF were added. Cells were harvested and luciferase activity was measured after 24 h (right). (C, left) The 200 bp sequence around site B on the TLR9 promoter with mapped NF-κB and ERα cis sites. (C, right) Site B was mutated at the cis ERα site (BER) and double mutation for NF-κB and ERα cis elements (BmER). (D, left) HK cells transduced with pLXSN, HPV16E7, or HPV6E7 were transfected with B200, B200m, BER, or BmER. 24 h after transfection luciferase activity was measured. (D, right) ChIP analyses of ERα phosphorylated and total forms and NF-κBp65 or p50 binding to site B on the TLR9 promoter in HK transduced ± HPV16E7. Data are representative of the mean of five or more independent experiments performed in triplicate, and error bars indicate SEM. **, P < 0.001 based on an unpaired Student’s t test.
Figure 4. The negative regulatory effect of HPV16 on the TLR9 promoter requires NF-κB and ERα binding to site B flanking sequences in human epithelial cells and HK. (A, top) Diagram illustrates the minimal B site promoter. (A, bottom) Human epithelial cervical cells were transfected with the NF-κB luciferase consensus site, the B minimal promoter or the control vector pTAL. 24 h after transfection 16QsV, control PV (native), CpG 2006, or TNF were added. Cells were harvested and luciferase activity was measured after 24 h. (B, top) Diagram depicting constructs including a 200 bp sequence of the TLR9 promoter containing the NF-κB cis element on site B WT (B200) or mutated (Bm). (B, bottom) C33A cells were transfected with B200 or B200m. 24 h after transfection, 16QsV or TNF were added. Cells were harvested and luciferase activity was measured after 24 h (right). (C, left) The 200 bp sequence around site B on the TLR9 promoter with mapped NF-κB and ERα cis sites. (C, right) Site B was mutated at the cis ERα site (BER) and double mutation for NF-κB and ERα cis elements (BmER). (D, left) HK cells transduced with pLXSN, HPV16E7, or HPV6E7 were transfected with B200, B200m, BER, or BmER. 24 h after transfection luciferase activity was measured. (D, right) ChIP analyses of ERα phosphorylated and total forms and NF-κBp65 or p50 binding to site B on the TLR9 promoter in HK transduced ± HPV16E7. Data are representative of the mean of five or more independent experiments performed in triplicate, and error bars indicate SEM. **, P < 0.001 based on an unpaired Student’s t test.CC BY-NC-SA · PubMed Central
Figure 5. ERα complexes with NF-κBp65 to suppress TLR9 transcription by 16QsV. (A, left) C33A cells were transfected with B200 and, 24 h later, shESR1 was introduced. 12 h after shESR1 introduction, cells were infected with 16QsV. Cells were harvested and luciferase activity was measured after 24 h. (A, right) qPCR and immunoblot analysis for TLR9 and ERα in the human epithelial cervical cells treated with shESR1. (B) C33A cells were transfected with a shRNA scramble for ERα (left) or with an shRNA for ERα (shESR1; right) for 24 h. Cells were then infected for 12 h with 16QsV and analyzed by ReChIP for NF-κBp50–ERα or NF-κBp65–ERα or NF-κBp65–p50 occupancy on site B of the TLR9 promoter. Data are representative of the mean of five or more independent experiments performed in triplicate; graphs show the mean ± SEM.
Figure 5. ERα complexes with NF-κBp65 to suppress TLR9 transcription by 16QsV. (A, left) C33A cells were transfected with B200 and, 24 h later, shESR1 was introduced. 12 h after shESR1 introduction, cells were infected with 16QsV. Cells were harvested and luciferase activity was measured after 24 h. (A, right) qPCR and immunoblot analysis for TLR9 and ERα in the human epithelial cervical cells treated with shESR1. (B) C33A cells were transfected with a shRNA scramble for ERα (left) or with an shRNA for ERα (shESR1; right) for 24 h. Cells were then infected for 12 h with 16QsV and analyzed by ReChIP for NF-κBp50–ERα or NF-κBp65–ERα or NF-κBp65–p50 occupancy on site B of the TLR9 promoter. Data are representative of the mean of five or more independent experiments performed in triplicate; graphs show the mean ± SEM.CC BY-NC-SA · PubMed Central
Figure 6. 16QsV induces closing of the chromatin structure on the TLR9 promoter from site B until the transcription start site. (A, left) ChIP using anti AceH4 or H3K4me3 histone antibodies was performed for site B using C33A cells infected with 16QsV for 6, 8, and 36 h. (A, right) C33A cells were treated as in A (left) except that 1 h after incubation with 16QsV, cells were treated with siRNA against HPV16E7. (B) Chromatin from C33A cells that had been incubated ± 16QsV for 24 h was analyzed by ChIP for AceH4 or H3K4me3 histones interacting with chromatin DNA along the TLR9 promoter. AceH4 or H3K4me3 binding to histones associated DNA upstream of site B on the TLR9 promoter were amplified by qPCR along the regions −1200 until −1. (C) HDAC1-3 binding to histone associated DNA of upstream of site B on the TLR9 promoter were amplified by qPCR along the regions −1200 until −1. (D) ReChIP for NF-κBp65–p50 or NF-κBp65–HDAC1-3 was performed on C33A cells treated with 16QsV for 36 h. Data are representative of three or more independent experiments; graphs shown are mean ± SEM from triplicate values.
Figure 6. 16QsV induces closing of the chromatin structure on the TLR9 promoter from site B until the transcription start site. (A, left) ChIP using anti AceH4 or H3K4me3 histone antibodies was performed for site B using C33A cells infected with 16QsV for 6, 8, and 36 h. (A, right) C33A cells were treated as in A (left) except that 1 h after incubation with 16QsV, cells were treated with siRNA against HPV16E7. (B) Chromatin from C33A cells that had been incubated ± 16QsV for 24 h was analyzed by ChIP for AceH4 or H3K4me3 histones interacting with chromatin DNA along the TLR9 promoter. AceH4 or H3K4me3 binding to histones associated DNA upstream of site B on the TLR9 promoter were amplified by qPCR along the regions −1200 until −1. (C) HDAC1-3 binding to histone associated DNA of upstream of site B on the TLR9 promoter were amplified by qPCR along the regions −1200 until −1. (D) ReChIP for NF-κBp65–p50 or NF-κBp65–HDAC1-3 was performed on C33A cells treated with 16QsV for 36 h. Data are representative of three or more independent experiments; graphs shown are mean ± SEM from triplicate values.CC BY-NC-SA · PubMed Central
Figure 7. Recruitment of epigenetic demethylating and deacetylating enzymes by ERα to site B on the TLR9 promoter in 16QsV human epithelial cells. (A) ReChIP for pERα–p65 or HDAC1-3 was performed on C33A cells treated with 16QsV for 24 h. (B, left) Immunoprecipation for ERα interactions with NF-κBp65 or HDAC1 was performed on chromatin fraction of C33A infected for 36 h with 16QsV. (B, right) Input controls. (C) ChIP using anti AceH4 histone antibodies was performed for site B on C33A cells infected with 16QsV for 24 h ± shESR1. (D) ChIP using anti H3K4me3 histone antibodies was performed for site B on C33A cells infected with 16QsV for 24 h ± shESR1. (E) Chromatin fraction Western blot analysis of JARID1B, ERα, or H3K4me3 expression in pLXSN or HPV16E7 ± shESR1-transduced HK. (F) ReChIP for pERα–p65 or pERα/HDAC1 or pERα/JARID1B was performed on C33A cells treated with 16QsV for 36 h. (G) ChIP using anti-JARID1B antibody was performed for site B on C33A cells infected with 16QsV for 24 h ± shScramble control sequence (shSCR) or shESR1. (H, left) Immunoprecipation for ERα interactions with NF-κBp65, p50, JARID1B, or HDAC1 was performed on chromatin fractions of C33A infected for 36 h with 16QsV ± DNase I treatment. (H, right) 10% of input loaded protein. (I, left) Oligo pulldown assay for site B, Bm, and BER using protein lysates from pLXSN or HPV16E7-transduced cells. Bound proteins were assessed by immunoblotting for NF-κBp65, p50, JARID1B, HDAC1, or ERα. (I, right) Input controls (10%). Data are representative of three or more independent experiments; graphs shown are the mean ± SEM from triplicate values.
Figure 7. Recruitment of epigenetic demethylating and deacetylating enzymes by ERα to site B on the TLR9 promoter in 16QsV human epithelial cells. (A) ReChIP for pERα–p65 or HDAC1-3 was performed on C33A cells treated with 16QsV for 24 h. (B, left) Immunoprecipation for ERα interactions with NF-κBp65 or HDAC1 was performed on chromatin fraction of C33A infected for 36 h with 16QsV. (B, right) Input controls. (C) ChIP using anti AceH4 histone antibodies was performed for site B on C33A cells infected with 16QsV for 24 h ± shESR1. (D) ChIP using anti H3K4me3 histone antibodies was performed for site B on C33A cells infected with 16QsV for 24 h ± shESR1. (E) Chromatin fraction Western blot analysis of JARID1B, ERα, or H3K4me3 expression in pLXSN or HPV16E7 ± shESR1-transduced HK. (F) ReChIP for pERα–p65 or pERα/HDAC1 or pERα/JARID1B was performed on C33A cells treated with 16QsV for 36 h. (G) ChIP using anti-JARID1B antibody was performed for site B on C33A cells infected with 16QsV for 24 h ± shScramble control sequence (shSCR) or shESR1. (H, left) Immunoprecipation for ERα interactions with NF-κBp65, p50, JARID1B, or HDAC1 was performed on chromatin fractions of C33A infected for 36 h with 16QsV ± DNase I treatment. (H, right) 10% of input loaded protein. (I, left) Oligo pulldown assay for site B, Bm, and BER using protein lysates from pLXSN or HPV16E7-transduced cells. Bound proteins were assessed by immunoblotting for NF-κBp65, p50, JARID1B, HDAC1, or ERα. (I, right) Input controls (10%). Data are representative of three or more independent experiments; graphs shown are the mean ± SEM from triplicate values.CC BY-NC-SA · PubMed Central
Figure 8. HPV16-positive cervical cancer lesions contain NF-κBp65–ERα nuclear complexes which bind to site B on the TLR9 promoter. Histology and immunofluorescence (IF) of normal cervical issue (A) and HPV16+ cervical cancer biopsies (B). Nuclear (white), TLR9 (blue), ERα (red), or NF-κBp65 (green). The box in the histology staining indicates which part of the slide was examined by IF. Normal (HPV−) and a neoplastic biopsy (HPV16+) from one representative patient out of eight tested with similar results is shown. Bars, 10 µm. (C) Histograms representing the cellular distribution for TLR9, ERα, and NF-κBp65 in normal (HPV−) and cancer cervical tissue (HPV16 positive by Apex screening). For each stained biopsy, six fields were examined and cytoplasmic or nuclear staining was counted manually and the percentage scored out of 100 cells. Data are representative of three independent experiments performed on 16 biopsies (eight normal and eight neoplastic); graphs shown are the mean ± SEM. ***, P < 0.0001. (D) Duolink analysis of NF-κBp65–ERα in normal versus cervical cancer tissue. DAPI marks the nucleus and the red dots represent NF-κBp65–ERα proximity ligation <40 nm distance. Shown are data from one out of five independent experiments that gave identical results. Represented here is one out of six fields examined for each section. Bars, 10 µm. (E) NF-κBp65 and ERα proximity interaction locality were estimated by counting the number of red dots manually and using the Duolink Image tool (Olink, Biosciences) present in three field sections on three normal versus three cervical cancer tissues. Data are representative of three independent experiments performed on six biopsies (normal and neoplastic); graphs shown are the mean ± SEM. (F) ChIP analysis was performed on normal cervical tissue and cervical cancer biopsies for NF-κBp65, p50, or ERα binding to site B on the TLR9 promoter (represented one experiment out of three ChIP, and qPCR for occupancy on site B was performed in duplicate three times on three normal vs. four cervical cancer tissues). Shown are data from six independent experiments performed in triplicate, and error bars indicate SEM. ***, P < 0.0001 based on an unpaired Student’s t test. (G) Duolink analysis of NF-κBp65–ERα in the cervical cancer cell line CaSki. DAPI marks the nucleus and the orange dots represent NF-κBp65–ERα proximity ligation <40 nm distance. Shown are data from one out of three independent experiments that gave identical results in which one of five fields were examined. Bars, 20 µm. (H) As in G, however cells were treated with a siRNA sequence for NF-κBp65 or small hairpin for ERα (as described in Fig. 5). Shown are data from one out of five independent experiments that gave identical results. Bars, 20 µm. (I, left) 63× zoom × 2 and ortho Z slices (3.3 µM) show nuclear penetration of the NF-κBp65 and ERα proximity ligation of <40 nm in scramble short hairpin for ERα-treated cells. Shown are data from one out of five fields examined and one out of five independent experiments that gave identical results. Bar, 20 µm. (I, right) Immunoblot demonstrating the efficiency of siRNA knockdown of NF-κBp65 and shESR1. Shown are data from one out three immunoblots performed.
Figure 8. HPV16-positive cervical cancer lesions contain NF-κBp65–ERα nuclear complexes which bind to site B on the TLR9 promoter. Histology and immunofluorescence (IF) of normal cervical issue (A) and HPV16+ cervical cancer biopsies (B). Nuclear (white), TLR9 (blue), ERα (red), or NF-κBp65 (green). The box in the histology staining indicates which part of the slide was examined by IF. Normal (HPV−) and a neoplastic biopsy (HPV16+) from one representative patient out of eight tested with similar results is shown. Bars, 10 µm. (C) Histograms representing the cellular distribution for TLR9, ERα, and NF-κBp65 in normal (HPV−) and cancer cervical tissue (HPV16 positive by Apex screening). For each stained biopsy, six fields were examined and cytoplasmic or nuclear staining was counted manually and the percentage scored out of 100 cells. Data are representative of three independent experiments performed on 16 biopsies (eight normal and eight neoplastic); graphs shown are the mean ± SEM. ***, P < 0.0001. (D) Duolink analysis of NF-κBp65–ERα in normal versus cervical cancer tissue. DAPI marks the nucleus and the red dots represent NF-κBp65–ERα proximity ligation <40 nm distance. Shown are data from one out of five independent experiments that gave identical results. Represented here is one out of six fields examined for each section. Bars, 10 µm. (E) NF-κBp65 and ERα proximity interaction locality were estimated by counting the number of red dots manually and using the Duolink Image tool (Olink, Biosciences) present in three field sections on three normal versus three cervical cancer tissues. Data are representative of three independent experiments performed on six biopsies (normal and neoplastic); graphs shown are the mean ± SEM. (F) ChIP analysis was performed on normal cervical tissue and cervical cancer biopsies for NF-κBp65, p50, or ERα binding to site B on the TLR9 promoter (represented one experiment out of three ChIP, and qPCR for occupancy on site B was performed in duplicate three times on three normal vs. four cervical cancer tissues). Shown are data from six independent experiments performed in triplicate, and error bars indicate SEM. ***, P < 0.0001 based on an unpaired Student’s t test. (G) Duolink analysis of NF-κBp65–ERα in the cervical cancer cell line CaSki. DAPI marks the nucleus and the orange dots represent NF-κBp65–ERα proximity ligation <40 nm distance. Shown are data from one out of three independent experiments that gave identical results in which one of five fields were examined. Bars, 20 µm. (H) As in G, however cells were treated with a siRNA sequence for NF-κBp65 or small hairpin for ERα (as described in Fig. 5). Shown are data from one out of five independent experiments that gave identical results. Bars, 20 µm. (I, left) 63× zoom × 2 and ortho Z slices (3.3 µM) show nuclear penetration of the NF-κBp65 and ERα proximity ligation of <40 nm in scramble short hairpin for ERα-treated cells. Shown are data from one out of five fields examined and one out of five independent experiments that gave identical results. Bar, 20 µm. (I, right) Immunoblot demonstrating the efficiency of siRNA knockdown of NF-κBp65 and shESR1. Shown are data from one out three immunoblots performed.CC BY-NC-SA · PubMed Central

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Cited by

Metadata

Authors
Hasan, U. A., Zannetti, C., Parroche, P., Goutagny, N., Malfroy, M., Roblot, G., Carreira, C., Hussain, I., Müller, M., Taylor-Papadimitriou, J., Picard, D., Sylla, B. S., Trinchieri, G., Medzhitov, R., & Tommasino, M.
Affiliations
  • Infections and Cancer Biology Group, International Agency for Research on Cancer, Lyon 69008, France 1
  • CIRI, Oncoviruses and Innate Immunity, INSERM U1111, Ecole Normale Supérieure, Université de Lyon, CNRS-UMR5308, Hospices Civils de Lyon, Lyon 69000, France 2
  • CRCL, UMR INSERM 1052 - CNRS 5286, Centre Léon Bérard, Lyon 69008, France 3
  • Division of Veterinary Biochemistry FVSc & AH, SK Alusteng, Kashmir 190006, India 4
  • Programme of Infection & Cancer, DKFZ, Heidelberg 69120, Germany 5
  • Breast Cancer Biology Group, King’s College London School of Medicine, Thomas Guy House, Guy’s Hospital, London SE1 9RT, England, UK 6
  • University of Geneva, 1211 Genève 4, Switzerland 7
  • Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702 8
  • Yale University School of Medicine, New Haven, CT 06510 9
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2013-06-10
Volume
210
Issue
7
Pages
1369-1387
ISSN
  • 1540-9538
  • 0022-1007
DOI
10.1084/jem.20122394
PMC
PMC3698525
Cited by
191
References
9
Language
en

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