Nuclear Receptor Co-repressor NCoR1 governs immune-tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation
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ABSTRACT:
PROVIDER: PRJEB55293 | ENA |
REPOSITORIES: ENA
Dataset's files
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| ERR10041023_1.fastq.gz | Fastqsanger.gz | |||
| ERR10041023_2.fastq.gz | Fastqsanger.gz | |||
| ERR10041024_1.fastq.gz | Fastqsanger.gz | |||
| ERR10041024_2.fastq.gz | Fastqsanger.gz | |||
| ERR10041025_1.fastq.gz | Fastqsanger.gz |
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Project description:In this study, we focused on demonstrating the metabolic aspect of NCoR1 in the regulation of dendritic cells (DCs) functionality. We report that NCoR1 deficient tolerogenic DCs meet their anabolic requirements through enhanced glycolysis and OxPhos, supported by FAO-driven oxygen consumption. Furthermore, individual and dual inhibition of glycolysis through HIF-1α inhibitor (KC7F2) and fatty acid oxidation through CPT1 inhibitor (etomoxir) significantly impaired the secretion of tolerogenic cytokines. To validate the same at the global mRNA level we did bulk RNA-seq to determine the differentially expressed genes in control and NCoR1 KD 6h CpG activated DCs with and without inhibitor treatment.
2024-01-01 | E-MTAB-12066 | biostudies-arrayexpress
Project description:Dendritic cells (DCs) undergo rapid metabolic reprogramming to generate signal-specific immune responses. The fine control of cellular metabolism underlying DC immune tolerance remains elusive. We have recently reported that NCoR1 ablation generates immune-tolerant DCs through enhanced IL-10, IL-27 and SOCS3 expression. In this study, we did comprehensive metabolic profiling of these tolerogenic DCs and identified that they meet their energy requirements through enhanced glycolysis and oxidative phosphorylation (OXPHOS), supported by fatty acid oxidation-driven oxygen consumption. In addition, the reduced pyruvate and glutamine oxidation with a broken TCA cycle maintains the tolerogenic state of the cells. Mechanistically, the AKT-mTOR-HIF-1α-axis mediated glycolysis and CPT1a-driven β-oxidation were enhanced in these tolerogenic DCs. To confirm these observations, we used synthetic metabolic inhibitors and found that the combined inhibition of HIF-1α and CPT1a using KC7F2 and etomoxir, respectively, compromised the overall transcriptional signature of immunological tolerance including the regulatory cytokines IL-10 and IL-27. Functionally, treatment of tolerogenic DCs with dual KC7F2 and etomoxir treatment perturbed the polarization of co-cultured naïve CD4+ T helper (Th) cells towards Th1 than Tregs, ex vivo and in vivo. Physiologically, the Mycobacterium tuberculosis (Mtb) infection model depicted significantly reduced bacterial burden in BMcDC1 ex vivo and in CD103+ lung DCs in Mtb infected NCoR1DC-/-mice. The spleen of these infected animals also showed increased Th1-mediated responses in the inhibitor-treated group. These findings suggested strong involvement of NCoR1 in immune tolerance. Our validation in primary human monocyte-derived DCs (moDCs) showed diminished NCOR1 expression in dexamethasone-derived tolerogenic moDCs along with suppression of CD4+T cell proliferation and Th1 polarization. Furthermore, the combined KC7F2 and etomoxir treatment rescued the decreased T cell proliferative capacity and the Th1 phenotype. Overall, for the first time, we demonstrated here that NCoR1 mediated control of glycolysis and fatty acid oxidation fine-tunes immune tolerance versus inflammation balance in murine and human DCs.
| S-EPMC9804250 | biostudies-literature
Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function. This SuperSeries is composed of the SubSeries listed below.
2024-02-12 | GSE237654 | GEO
Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
2024-02-12 | GSE237653 | GEO
Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
2024-02-12 | GSE242671 | GEO
Project description:NCoR1 (Nuclear receptor Co-Repressor) and SMRT (Silencing Mediator of Retinoid and Thyroid hormone receptor) are well-recognized coregulators of nuclear receptor (NR) action. However, their unique roles in the regulation of thyroid hormone (TH) signaling in specific cell types have not been determined. To accomplish this we generated a mouse model that lacked function of either NCoR1 or SMRT or both in the liver only. Despite both corepressors being present in the liver, SMRT had no ability to regulate TH signaling when deleted in either euthyroid or hypothyroid animals. In contrast, disruption of NCoR1 action confirmed that it is the principal mediator of TH sensitivity in vivo. While SMRT played little role in TH signaling alone, when disrupted in combination with NCoR1 it greatly accentuated the activation of hepatic lipogenesis regulated by NCoR1. Thus, corepressor specificity exists in vivo and NCoR1 is the principal regulator of TH action in the liver. However, both NCoR1 and SMRT collaborate to control hepatic lipogenesis and lipid storage, which likely reflects their cooperative activity in regulating the action of multiple NRs including the thyroid hormone receptor (TR). RNA was extracted from livers from 3 individual mice for each group (Double-floxed, Liver specific-SMRT knock out, and Liver specific-double knock out); all were euthyroid, female mice
2014-11-21 | E-GEOD-54192 | biostudies-arrayexpress
Project description:Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with components of the Nuclear Receptor Corepressor Complex 1 and 2 (NCoR1 and NCoR2). Upon attenuation of Fgf signalling, unphosphorylated, nuclear Erf recruits the NCoR1/2 complex to key trophoblast genes, brings about their transcriptional silencing and facilitates differentiation and placental development.
2023-04-26 | PXD037892 | Pride
Project description:Fine-tuning modulation of oxidation-mediated posttranslational control of Bradyrhizobium diazoefficiens FixK2 transcription factor
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Project description:This study was designed to identify putative NCoR1-interacting proteins that might regulate the mitochondrial biogenesis process. To do that, MEF cells were transiently transfected with plasmid expressing either pcDNA-GFP-FLAG (control) or pCMX-NCoR1-FLAG and subjected to co-IP and identification of interacting proteins by liquid chromatography tandem mass spectrometry (LC-MS/MS) (LTQ Velos Orbitrap).
2023-07-20 | PXD040945 | Pride
Project description:NCOR1 is a trancriptional coregulator and has been demonstrated to modulate the acitivities of multiple transcription factors in many cell types. However, the function of NCOR1 in vascular smooth muscle cells (VSMCs) is unclear. We aimed to explore the effect of NCOR1 deficiency on gene expression in VSMCs and phenoypic modulation of VSMCs. Therefore, we constructed smooth-muscle specific NCOR1 knockout mice and isolated primary VSMCs for RNA-sequencing.
2021-10-13 | GSE185635 | GEO