TonEBP/NFAT5 regulates inflammatory gene expression in nucleus pulposus cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE86552 | GEO | 2016/11/08
SECONDARY ACCESSION(S): PRJNA342179
REPOSITORIES: GEO
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Project description:RNA sequencing of nucleus pulposus cells transduced with shRNA (control or TonEBP-targeted) and either untreated or treated with TNF-a (24h)
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Project description:TonEBP is a transcription factor that promotes cellular accumulation of organic osmolytes in the hypertonic renal medulla by stimulating expression of its target genes. Genetically modified animals with deficient TonEBP activity in the kidney suffer from severe medullary atrophy in association with cell death, demonstrating that TonEBP is essential for the survival of the renal medullary cells. Using both TonEBP knockout cells and RNA interference of TonEBP, we found that TonEBP promoted cellular adaptation to hypertonic stress. Microarray analyses revealed that genetic response to hypertonicity was dominated by TonEBP in that expression of totally different sets of genes was increased by hypertonicity in those cells with TonEBP vs. those without TonEBP activity. Out of over 100 potentially new TonEBP regulated genes, we selected 7 for further analyses and found that their expression was all dependent on TonEBP. RNA interference experiments showed that some of these genes – asporin, insulin-like growth factor-binding protein 5 and 7, and an extracellular lysophosphlipase D – plus Hsp70, a known TonEBP target gene, contributed to the adaptation to hypertonicity without promoting organic osmolyte accumulation. We conclude that TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress in addition to organic osmolyte accumulation. Quadruplicate samples were collected for each condition and then pooled into a single sample for hybridization to microarrays.
2010-12-10 | E-GEOD-25816 | biostudies-arrayexpress
Project description:TonEBP is a transcription factor that promotes cellular accumulation of organic osmolytes in the hypertonic renal medulla by stimulating expression of its target genes. Genetically modified animals with deficient TonEBP activity in the kidney suffer from severe medullary atrophy in association with cell death, demonstrating that TonEBP is essential for the survival of the renal medullary cells. Using both TonEBP knockout cells and RNA interference of TonEBP, we found that TonEBP promoted cellular adaptation to hypertonic stress. Microarray analyses revealed that genetic response to hypertonicity was dominated by TonEBP in that expression of totally different sets of genes was increased by hypertonicity in those cells with TonEBP vs. those without TonEBP activity. Out of over 100 potentially new TonEBP regulated genes, we selected 7 for further analyses and found that their expression was all dependent on TonEBP. RNA interference experiments showed that some of these genes – asporin, insulin-like growth factor-binding protein 5 and 7, and an extracellular lysophosphlipase D – plus Hsp70, a known TonEBP target gene, contributed to the adaptation to hypertonicity without promoting organic osmolyte accumulation. We conclude that TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress in addition to organic osmolyte accumulation.
2010-12-10 | GSE25816 | GEO
Project description:To evaluate the effect of Hypoxia-inducible factor 1-alpha inhibitor (HIF-1) in nucleus pulposus (NP) cells, human NP cells were lentivirally transduced with either control or FIH-1 targeted shRNA. Gene expression changes between samples from control and FIH-1 silenced cells were evaluated using a microarray. Primary NP cells were isolated from human discs and grown in culture. Cells were transduced with either control or FIH-1 targeting shRNA constructs. Silencing of FIH-1 was confirmed for each set using qRT-PCR and Western blot. Total RNA from NP cells was used for RNA extraction and hybridization on the Affymetrix microarray. Control samples: C1, C2, and C3 and FIH-1-silenced samples: E1, E2, and E3.
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Project description:To evaluate the effect of Hypoxia-inducible factor 1-alpha inhibitor (HIF-1) in nucleus pulposus (NP) cells, human NP cells were lentivirally transduced with either control or FIH-1 targeted shRNA. Gene expression changes between samples from control and FIH-1 silenced cells were evaluated using a microarray.
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Project description:Intervertebral disc degeneration (IDD) causes chronic back pain and is linked to production of proinflammatory molecules by nucleus pulposus (NP) and other disc cells. Activation of tonicity-responsive enhancer-binding protein (TonEBP)/NFAT5 by non-osmotic stimuli, including proinflammatory molecules, occurs in cells involved in immune response. However, whether inflammatory stimuli activate TonEBP in NP cells and whether TonEBP controls inflammation during IDD is unknown. We show that TNF-α, but not IL-1β or LPS, promoted nuclear enrichment of TonEBP protein. However, TNF-α-mediated activation of TonEBP did not cause induction of osmoregulatory genes. RNA sequencing showed that 8.5% of TNF-α transcriptional responses were TonEBP-dependent and identified genes regulated by both TNF-α and TonEBP. These genes were over-enriched in pathways and diseases related to inflammatory response and inhibition of matrix metalloproteases. Based on RNA-sequencing results, we further investigated regulation of novel TonEBP targets CXCL1, CXCL2, and CXCL3 TonEBP acted synergistically with TNF-α and LPS to induce CXCL1-proximal promoter activity. Interestingly, this regulation required a highly conserved NF-κB-binding site but not a predicted TonE, suggesting cross-talk between these two members of the Rel family. Finally, analysis of human NP tissue showed that TonEBP expression correlated with canonical osmoregulatory targets TauT/SLC6A6, SMIT/SLC5A3, and AR/AKR1B1, supporting in vitro findings that the inflammatory milieu during IDD does not interfere with TonEBP osmoregulation. In summary, whereas TonEBP participates in the proinflammatory response to TNF-α, therapeutic strategies targeting this transcription factor for treatment of disc disease must spare osmoprotective, prosurvival, and matrix homeostatic activities.
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Project description:Our studies show that TonEBP-deficiency causes pronounced degeneration of all three intervertebral disc compartments with greater incidence of herniation in the mouse. The disc phenotype is marked by extracellular matrix remodeling, actin cytoskeleton rearrangements, and suppressed proinflammatory gene expression, advancing our understanding of the contributions of TonEBP in intervertebral disc homeostasis and disease. We used microarray to explore the transcriptomics of differentially expressed genes of annulus fibrosus (AF) and nucleus pulposus (NP) tissue in TonEBP haploinsufficient mice on a C57BL/6 background.
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