Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1125303 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29457713_1.fastq.gz | Fastqsanger.gz | |||
| SRR29457713_2.fastq.gz | Fastqsanger.gz | |||
| SRR29457714_1.fastq.gz | Fastqsanger.gz | |||
| SRR29457714_2.fastq.gz | Fastqsanger.gz | |||
| SRR29457715_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic landscape remodeled by the transcription factor RBPJ promotes tumor-infiltrating T cell exhaustion
2024-06-18 | PXD053189 |
Project description:The suppression of PDL1 expression through inhibition of the assembly of the RBPJ transcription complex has been shown to alleviate T cell exhaustion. However, the specific role of RBPJ in T cells, particularly its potential involvement in the anti-tumor activity of T cells, remains largely unexplored. In this research, immunoprecipitation was employed to identify HUWE1 as the E3 ubiquitin ligase for RBPJ. The integration of CUT&Tag, ChIP/ATAC-qPCR, immunoprecipitation, and flow cytometry analysis revealed that RBPJ induced T cell dysfunction through alterations in the epigenetic landscape, enhancement of transcriptional activity, and modulation of histone methylation/acetylation on exhaustion genes. Additionally, virtual screening and molecular dynamics simulation were utilized to demonstrate that Acarbose disrupted the function of RBPJ by reshaping the assembly of the RBPJ-RUVBL1/DNA ternary complex. Our findings elucidated the induction of RBPJ expression in exhausted T cells and the exacerbation of T cell exhaustion by RBPJ. Additionally, the molecular conformational changes of the RBPJ transcriptional complex induced by Acarbose shed light on the potential of targeted inhibition of T cell exhaustion for the treatment of hepatocellular carcinoma.
2024-06-20 | PXD053266 |
Project description:Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. At the molecular level, the key components of the Notch pathway are the NOTCH-family receptors, the ligands of the DSL (Delta, Serrate, Lag-2) family and the transcription factor CSL [CBF1/RBPJ, Su(H), Lag-1]. Upon ligand binding, the NOTCH Intra-Cellular Domain (NOTCH ICD) translocates into the nucleus and forms a complex with RBPJ to activate the transcription of target genes. In the absence of NOTCH ICD, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 as a novel interactor of RBPJ. We discovered that L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and its co-factor KDM1A [lysine (K)-specific demethylase 1A] to the promoters/enhancers of Notch target genes to promote H3K4me2 demethylation and transcriptional repression. In three distinct cell contexts in which Notch signaling governs cell fate, i.e., mature T-cells as well as brain and breast tumor cells, the loss of L3MBTL3 results in the de-repression of Notch target genes. Finally, the genetic analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ/Su(H)/lag-1 and L3MBTL3/dL(3)mbt/lin-61 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.
2017-10-17 | PXD004196 | Pride
Project description:Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, We used DNA-protein pull-down using Nrg1 enhancer sequence as bait followed by LC/MS and identified RBPJ as a key component of the Nrg1 enhanceosome. We show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, forming enhanceosome complexes where RBPJ, P300, and SETD1A are recruited to upregulate Nrg1 expression.
2023-01-29 | PXD038668 | Pride
Project description:Hyperglycemia is a risk factor for breast cancer-related morbidity and mortality. Hyperglycemia induces Neuregulin 1 (Nrg1) overexpression in breast cancer, which subsequently promotes tumor progression. However, molecular mechanisms underlying hyperglycemia-induced Nrg1 overexpression remain poorly understood. Here, We used DNA-protein pull-down using Nrg1 enhancer sequence as bait followed by LC/MS and identified RBPJ as a key component of the Nrg1 enhanceosome. We show that hyperglycemia causes active histone modifications at the Nrg1 enhancer, forming enhanceosome complexes where RBPJ, P300, and SETD1A are recruited to upregulate Nrg1 expression.
2022-12-21 | MSV000090951 | MassIVE
Project description:Dysregulation of the Notch-RBPJ signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified FBXO42 as a novel RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine (K) 175 via K63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 ligase activity attenuates the Notch signaling-related leukemia development in vivo. Taken together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes, but also provide insights into the therapeutic intervention of the Notch pathway for leukemia treatment.
2022-10-13 | PXD034938 | Pride
Project description:Glioblastomas coopt stem cell regulatory pathways to maintain brain tumor initiating cells (BTICs), also known as cancer stem cells. Notch signaling has been a molecular target in BTICs, but Notch antagonists have demonstrated limited efficacy in clinical trials. RBPJ is considered a central transcriptional mediator of Notch activity. Here, we report that pharmacologic Notch inhibitors were less effective than targeting RBPJ in suppressing tumor growth. While Notch inhibitors decreased canonical Notch gene expression, RBPJ regulated a distinct profile of genes critical to BTIC stemness and cell cycle progression. RBPJ was preferentially expressed by BTICs and required for BTIC self-renewal and tumor growth. MYC, a key BTIC regulator, bound the RBPJ promoter and treatment with a BET family bromodomain inhibitor decreased MYC and RBPJ expression. Proteomic studies demonstrated that RBPJ binds CDK9, a component of P-TEFb (positive transcription elongation factor), to target gene promoters, enhancing transcriptional elongation. Collectively, RBPJ links MYC and transcriptional control through CDK9, providing potential nodes of fragility for therapeutic intervention, potentially distinct from Notch.
2016-05-01 | GSE79735 | GEO
Project description:Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an “alternatively activated” phenotype. TAM differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy. MMTV-PyMT mice (Jackson Laboratory) were backcrossed to the C57BL/6 background for 10 generations. Rbpjfl/fl mice were provided by Tasuku Honjo and crossed to CD11ccre mice provided by Boris Reizis. Littermate controls were used in all experiments when possible. All mice were maintained in a specific pathogen-free facility and animal experimentation was conducted in accordance with institutional guidelines. In the MMTV-PyMT spontaneous mammary tumor model, we found the key Notch transcriptional regulator, RBPJ, to be required for TAM terminal differentiation from inflammatory monocytes. The bulk myeloid cell population that remains in CD11cCreRbpj fl/fl mice (the cells in "Rbpj KO" samples), represents monocytes that have begun their differentiation into macrophages, but are unable to terminally differentiate due to the lack of Rbpj.
2014-04-18 | E-GEOD-56755 | biostudies-arrayexpress