Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pharmacological intervention of PRMT5 links the E2F pathway with tumor associated antigens derived from the non-coding genome

ABSTRACT: E2F activity impacts on an extensive gene network mediated in part by PRMT5-dependent arginine methylation which widens its functional role in gene expression control. We show here that the PRMT5-E2F1 axis has an additional and unexpected level of control through facilitating expression of the non-coding genome where long non-coding (lnc) genes are direct targets for PRMT5 and E2F1. The expression of some lncRNAs results in their translation into small proteins, which then give rise to peptides which populate the MHC class I antigen presentation machinery. Pharmacological inhibition of PRMT5 alters the expression of lncRNA genes and thereby the repertoire lncRNA-derived peptides presented as MHC bound peptides. Delayed tumor growth upon PRMT5 inhibition reflects an influx of lncRNA peptide-specific cytotoxic CD8 T cells. When presented to the immune system as a stand-alone therapeutic vaccine, lncRNA-derived MHC-bound peptides are immunogenic and drive a potent anti-tumor T cell response with a significant delay in tumor growth. Our results show that the PRMT5 through its control of the E2F pathway influences expression of the non-coding genome and derived peptides presented to the immune system, which can subsequently be harnessed to deliver an effective stand-alone cancer vaccine. These results have important implications for deploying pharmacological intervention to manipulate gene expression and antigen presentation to the immune system and deploying new types of cancer vaccine. They also indicate that cell cycle control through the E2F pathway is intimately connected with immune recognition.

ORGANISM(S): Mus musculus

PROVIDER: GSE181401 | GEO | 2023/01/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Identification of antigens presented by MHC for vaccines against tuberculosis

Project description:The immune response against tuberculosis relies, at least in part, on CD4+ T cells. Protective vaccines require the induction of antigen-specific CD4+ T cells via mycobacterial peptides presented by MHC class-II in infected macrophages. We have purified MHC class-I and MHC-II peptides and analysed them by mass spectrometry. We have successfully identified 97 mycobacterial peptides presented by MHC-II and 54 presented by MHC-I, from 76 and 41 antigens, respectively. The sequences of selected peptides were confirmed by spectral match validation and immunogenicity evaluated by IFN-gamma ELISpot against peripheral blood mononuclear cells from volunteers vaccinated with BCG, M.tb latently infected subjects or patients with tuberculosis disease. Three antigens were expressed in viral vectors, and evaluated as vaccine candidates alone or in combination in a murine aerosol M.tb challenge model. When delivered in combination, the three candidate vaccines conferred significant protection in the lungs and spleen compared with BCG alone, demonstrating proof-of-concept for this unbiased approach to identifying novel candidate antigens.

2020-01-08 | E-MTAB-8057 | biostudies-arrayexpress

Transcription profiling and proteomic profiling of human B-LCL cell lines (TAP1/2 +/+ and TAP1/2 -/-) to analyse HLA peptide repertoire

Project description:The TAP transporter is responsible for transferring cytosolic peptides into the ER where they can be loaded onto MHC molecules. Deletion of TAP results in a drastic reduction of MHC surface expression and alters the presented peptide pattern. Using the TAP deficient cell line LCL721.174 and its TAP expressing progenitor cell line LCL721.45, we have identified and quantified more than 160 HLA ligands, 50 out of which were presented TAP independently. Peptides which were predominantly presented on the TAP deficient LCL721.174 cell line had a decreased MHC binding affinity according to their SYFPEITHI and BIMAS score. About half of the identified TAP independently presented peptides were not derived from signal sequences and may partly be generated by the proteasome. Furthermore, we have excluded that different HLA presentation ratios were due to varying expression of the respective protein or due to changes in the antigen loading complex. Features of TAP-independently presented peptides as well as proteasomal contribution to their generation provides an insight into basic immunological mechanisms. Experiment Overall Design: Two B-LCL cell lines (TAP1/2 +/+ and TAP1/2 -/-) were compared in their gene and protein expression as well as in their HLA peptide repertoire

2008-06-16 | E-GEOD-9437 | biostudies-arrayexpress

Features of TAP independently presented MHC ligands revealed by quantitative mass spectrometry.

Project description:The TAP transporter is responsible for transferring cytosolic peptides into the ER where they can be loaded onto MHC molecules. Deletion of TAP results in a drastic reduction of MHC surface expression and alters the presented peptide pattern. Using the TAP deficient cell line LCL721.174 and its TAP expressing progenitor cell line LCL721.45, we have identified and quantified more than 160 HLA ligands, 50 out of which were presented TAP independently. Peptides which were predominantly presented on the TAP deficient LCL721.174 cell line had a decreased MHC binding affinity according to their SYFPEITHI and BIMAS score. About half of the identified TAP independently presented peptides were not derived from signal sequences and may partly be generated by the proteasome. Furthermore, we have excluded that different HLA presentation ratios were due to varying expression of the respective protein or due to changes in the antigen loading complex. Features of TAP-independently presented peptides as well as proteasomal contribution to their generation provides an insight into basic immunological mechanisms. Keywords: differential mass spectrometry, TAP independent, antigen presentation

2007-10-27 | GSE9437 | GEO

Arginine methylation controls cell proliferation by integrating E2F activity with the splicing machinery (RNA-seq data set)

Project description:Residue-specific arginine methylation (meR) on the E2F1 subunit plays an essential role in determining whether cell cycle progression or apoptosis ensues, although the molecular pathways underpinning the effects of methylation remain obscure. We report here that the methylation events on E2F1 have a direct impact on the mechanisms which underpin gene expression control. Specifically, the PRMT5-mediated symR mark not only influences the transcription repertoire of genes targeted by E2F1, but also endows E2F1 with the ability to regulate RNA splicing. This occurs through tudor domain protein p100/TSN which reads the symR mark on E2F1, and thereby enables a distinct set of RNA to be alternatively spliced. The p100/TSN-E2F1 complex binds alternatively spliced RNAs, with many RNAs derived from E2F target genes connected with proliferation and cancer.

2019-07-02 | GSE111960 | GEO

Arginine methylation controls cell proliferation by integrating E2F activity with the splicing machinery (RIP-seq data set)

2019-07-02 | GSE111959 | GEO

PRMT5 promotes cancer cell migration and invasion through the E2F pathway

Project description:We identified distinct sets of genes under the control of PRMT5 and E2F1. Some of the most highly regulated genes, such as cortactin/CTTN, influenced cell migration, invasion and adherence. We characterised the functional role of the cortactin/CTTN gene, which enabled PRMT5 through E2F1 to promote cellular migration and invasion, whilst decreasing cellular adherence. Most significantly, there was a striking coincidence between the expression of PRMT5 and E2F1 in certain human tumours, and elevated levels of PRMT5, E2F1 and cortactin/CTTN correlated with poor prognosis disease. Our results suggest a causal relationship between PRMT5, E2F1 and the migration and invasion of cancer cells, thereby highlighting an important pathway that contributes to the cancer biology of tumour cells.

2020-07-28 | GSE142430 | GEO

Cancer-relevant alternative RNA splicing events driven by the PRMT5-E2F1 axis in high risk neuroblastoma

Project description:Neuroblastoma (NB) is a devastating childhood cancer that remains clinically unmet. There is an urgency to develop new approaches to treat the disease. Protein arginine methyltransferase (PRMT5) is over-expressed in a wide variety of cancers and has been implicated with a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. Here, we have investigated the relevance of the interplay between PRMT5 and E2F1 in neuroblastoma and found that elevated expression occurs in poor prognosis high-risk disease. Cell lines derived from NB that recapitulate high PRMT5 and E2F1 expression exhibit increased levels of alternative RNA splicing compared to their low expression cell counterparts. Cancer-relevant exon-skipping events in apoptotic genes were apparent in high expressing NB cells which resulted in protein isoforms with decreased apoptotic activity. Pharmacological inhibition of PRMT5 or inactivation of E2F1 activity reduced exon skipping and reinstated normal apoptotic activity. Our findings show that a cancer relevant alternative splicing programme desensitises high risk NB to apoptosis. The critical role ascribed to PRMT5 and E2F1 in attaining the alterative RNA splicing programme equally identifies PRMT5 as a potential therapeutic target for neuroblastoma disease.

2024-09-14 | GSE243989 | GEO

Comparison of the Translatome of normal alveolar type 2 organoids and lung adenocarcinoma organoids

Project description:In an effort to understand the differences between the presented repertoire of MHC-I peptides in healthy lung tissue and tumor bearing lung, we evaluated the translatome of AT2 cells and tumor cells.

2022-07-08 | GSE178944 | GEO

Transcription profiling of mouse small intestines

Project description:Rb and E2F are thought to play antagonistic roles in celll proliferation. However, this model is based mostly from in vitro cell culture systems. We used small intestines to test this model in vivo. We found that deletion of E2f1-3 in the small intestine of mice suppressed the ectopic expression of E2F targets and cell proliferation caused by Rb-deficiency. Surprisingly, E2f1-3 deletion failed to arrest the proliferation of intestinal cells containing an intact Rb gene, and instead led to E2F target derepression and apoptosis. Experiment Overall Design: Total RNA of crypts and villi from wild-type, Rb-/-, E2f1-/-, E2f2-/-, E2f3-/-, E2f1-/-, E2f2-/-, and E2f3-/- small intestines. Small intestines were harvested 7 days after mice were injected intraperitoneally with beta-napthoflavone.

2010-01-19 | E-GEOD-16454 | biostudies-arrayexpress

MHC class I loaded ligands from breast cancer cell lines: A potential HLA-I-typed antigen collection

Project description:We sought to build a catalog of epitopes presented by breast cancers using a renewable resource of well-characterized breast cancer cell lines. Starting from 70 breast cancer cell lines, we measured MHC class I abundance and used pre-existing RNAseq data to identify either HLA-A*02 or MHC class I-positive cell lines. For 20 of these cell lines, we used “reverse” immunogenetics, in which MHC class I-loaded peptides are recovered and their sequences are determined by mass spectrometry. We identified more than 2,700 unique MHC class I-bound peptides from a panel of basal, luminal, and claudin-low subtype of cell lines. HLA-A*02 binding prediction across all tested cell lines revealed a model which described the distribution of HLA-A*02-binding peptides and allowed us to identify those peptides most likely to be presented on HLA-A*02. Comparing the peptides that we identified to published literature found that more than 1500 peptides had been identified in previous studies and that 18 of these peptides have been shown to be immunogenic. Overall, this high throughput identification of MHC class I-loaded peptides is an effective strategy for systematic characterization of cancer epitopes and could be employed in a design of multipeptide-based anticancer vaccine.

2018-01-16 | PXD006406 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data