HPVE6-USP46 Mediated Cdt2 Stabilization Reduces Set8 Mediated H4K20-Methylation to Induce Gene Expression Changes
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PROVIDER: PRJNA789318 | ENA |
REPOSITORIES: ENA
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Project description:Cervical cancer is one of the most common cancers in women. More than 95% of the cervical cancers are caused by the human papilloma viruses. Earlier we had identified a protein target, USP46 that can be inhibited to block the cancer growth. We found that the viral E6 and human USP46 complex increases the levels of Cdt2 in cervical cancers. In this paper we compared real cervical tumors with matched normal tissue from same patients and found that the effects of E6 mediated USP46 activation are indeed reflected as increased levels of Cdt2 and decreased levels of Set8 protein in the real tumors. We also found that the HPV protein E6 alone can stimulate the enzymatic activity of human USP46. By doing this it activates several cellular pathways that are required for the growth of cancers. One such pathway is the EGFR pathway that is normally upregulated in cervical cancers. We find that E6-USP46 contributes to the activation of EGFR by inducing epigenetic changes on the DNA by degrading the Set8 protein. These findings illuminate the role of viral E6 protein in inducing cancers and substantiate the candidature of USP46 as a drug target for HPV induced cancers.
2021-12-20 | GSE191010 | GEO
Project description:Histone methylation has an important role in transcriptional regulation. However, unlike H3K4 and H3K9 methylation, the role of H4K20 mono-methylation (H4K20me-1) in transcriptional regulation remains unclear. Here we show that Wnt3a specifically stimulates H4K20 mono-methylation at TBE (TCF-binding element) via the histone methylase SET8. Additionally, SET8 is crucial for activation of the Wnt reporter gene and target genes in both mammalian cells and zebrafish. Furthermore, SET8 interacts with TCF4/LEF1 directly, and this interaction is regulated by Wnt3a. Therefore, we conclude that SET8 is a Wnt signaling mediator and is recruited by LEF1/TCF4 to regulate the transcription of Wnt-activated genes, possibly via H4K20 mono-methylation at the target gene promoters. Our findings also indicate that H4K20me-1 is a marker for gene transcription activation, at least in canonical Wnt signaling. This chip experiment was carried out to find out how many genes would be regulated by SET8 after Wnt3a CM stimulated HEK293 cells. Total RNA was extracted from HEK293 cells after siRNA transfection (control or SET8 shRNA) for about 40 hours and then induced with Control or Wnt3a CM for 7 hours using TRIzol (Invitrogen) and the RNeasy kit (Qiagen). Three pairs of samples: si-control + control CM / si-control + Wnt3a CM 7 h / si-SET8 + Wnt3a CM. Samples were amplified and labeled using a NimbleGen One-Color DNA Labeling Kit.
2010-12-29 | E-GEOD-24708 | biostudies-arrayexpress
Project description:Histone methylation has an important role in transcriptional regulation. However, unlike H3K4 and H3K9 methylation, the role of H4K20 mono-methylation (H4K20me-1) in transcriptional regulation remains unclear. Here we show that Wnt3a specifically stimulates H4K20 mono-methylation at TBE (TCF-binding element) via the histone methylase SET8. Additionally, SET8 is crucial for activation of the Wnt reporter gene and target genes in both mammalian cells and zebrafish. Furthermore, SET8 interacts with TCF4/LEF1 directly, and this interaction is regulated by Wnt3a. Therefore, we conclude that SET8 is a Wnt signaling mediator and is recruited by LEF1/TCF4 to regulate the transcription of Wnt-activated genes, possibly via H4K20 mono-methylation at the target gene promoters. Our findings also indicate that H4K20me-1 is a marker for gene transcription activation, at least in canonical Wnt signaling. This chip experiment was carried out to find out how many genes would be regulated by SET8 after Wnt3a CM stimulated HEK293 cells.
2010-12-29 | GSE24708 | GEO
Project description:Ubiquitin-mediated proteolysis play a significant role in various biological processes including transcription, DNA repair and cell cycle progression. The identification of Set8 and Set8b (a splice isoform) histone H4K20 methyl transferase as a substrate for the cullin-based ubiquitin ligase (CRL4-Cdt2) demonstrate that this pathway plays a significant role in promoting cell cycle progression, specifically promoting G2 progression. This study investigate the effect of failure to degrade Set8 in S-phase of the cell cycle via CRL4-Cdt2 on gene expression. We used microarrays to detail the effect of the expression of stable form of Set8b H4K20 mono-methyl transferase (Set8b_deltaPIP2) on gene expression Human osteosarcoma-derived human cells were transduced with retroviruses encoding either wt-Set8b or a mutant of Setb8 which is resistant to degradation via CRL4-Cdt2 ubiquitin ligase complex (Set8b_deltaPIP2) or with an a control pMSCV empty virus. 5 days after transduction, cells were harvested and the RNA was extracted by Trizol (Invitrogen) and hybridized to the affymetrix chips array.
2010-09-18 | E-GEOD-24170 | biostudies-arrayexpress
Project description:Ubiquitin-mediated proteolysis play a significant role in various biological processes including transcription, DNA repair and cell cycle progression. The identification of Set8 and Set8b (a splice isoform) histone H4K20 methyl transferase as a substrate for the cullin-based ubiquitin ligase (CRL4-Cdt2) demonstrate that this pathway plays a significant role in promoting cell cycle progression, specifically promoting G2 progression. This study investigate the effect of failure to degrade Set8 in S-phase of the cell cycle via CRL4-Cdt2 on gene expression.
2010-09-18 | GSE24170 | GEO
Project description:Microtubules are critical for mitosis, cell motility, and protein and organelle transport, and are a validated target for anticancer drugs. However, tubulin regulation and recruitment in these cellular processes is less understood. Post-translational modifications of tubulin are proposed to regulate microtubule functions and dynamics. Although many such modifications have been investigated, tubulin methylations and enzymes responsible for methylation have only recently begun to be described. Here we report that N-lysine methyl transferase KMT5A (SET8/PR‑Set7), which methylates histone H4K20, also methylates α‑tubulin. Furthermore, the transcription factor LSF binds both tubulin and SET8, and enhances α-tubulin methylation in vitro, countered by FQI1, a specific small molecule inhibitor of LSF. Thus, the three SET8, LSF, and tubulin, all essential for mitotic progression, interact with each other. Overall, these results point to dual functions for both SET8 and LSF not only in chromatin regulation, but also for cytoskeletal modification.
2020-02-28 | PXD014257 | Pride
Project description: Not available
| S-EPMC8750077 | biostudies-literature
Project description:In mammalian cells, SET8 mediated Histone H4 Lys 20 monomethylation (H4K20me1) has been implicated in regulating mitotic condensation, DNA replication, DNA damage response, and gene expression. Here we show SET8, the only known enzyme for H4K20me1 is post-translationally poly ADP-ribosylated by PARP1 on lysine residues. PARP1 interacts with SET8 in a cell cycle- dependent manner. Poly ADP-ribosylation on SET8 renders it catalytically compromised and it undergoes degradation via ubiquitylation pathway. Knockdown of PARP1 shifted the relative dynamic equilibrium of H4K20me2 to H4K20me3 in cells. Overexpression or knockdown of PARP1 led to aberrant H4K20me1 domains genome-wide, impacting Wnt signaling pathways genes and transcription factor binding site enrichment. Therefore, SET8 mediated chromatin remodeling in mammalian cells are influenced by poly ADP-ribosylation by PARP1.
2022-11-17 | GSE188744 | GEO
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