HDAC9-mediated Epithelial Cell Cycle Arrest in G2/M Contributes to Kidney Fibrosis
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ABSTRACT:
PROVIDER: PRJNA897857 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22175844_1.fastq.gz | Fastqsanger.gz | |||
| SRR22175844_2.fastq.gz | Fastqsanger.gz | |||
| SRR22175845_1.fastq.gz | Fastqsanger.gz | |||
| SRR22175845_2.fastq.gz | Fastqsanger.gz | |||
| SRR22175846_1.fastq.gz | Fastqsanger.gz |
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Project description:Renal tubular epithelial cells (TECs) play a key role in kidney fibrosis by mediating cycle arrest at G2/M. However, the key HDAC isoforms and the underlying mechanism that are involved in G2/M arrest of TECs remain unclear. Here, we find that Hdac9 expression is significantly induced in the mouse fibrotic kidneys, especially in proximal tubules, induced by aristolochic acid nephropathy (AAN) or unilateral ureter obstruction (UUO). Tubule-specific deletion of HDAC9 or pharmacological inhibition by TMP195 attenuates epithelial cell cycle arrest in G2/M, then reduces production of profibrotic cytokine and alleviates tubulointerstitial fibrosis in male mice. In vitro, knockdown or inhibition of HDAC9 alleviates the loss of epithelial phenotype in TECs and attenuates fibroblasts activation through inhibiting epithelial cell cycle arrest in G2/M. Mechanistically, HDAC9 deacetylates STAT1 and promotes its reactivation, followed by inducing G2/M arrest of TECs, finally leading to tubulointerstitial fibrosis. Collectively, our studies indicate that HDAC9 may be an attractive therapeutic target for kidney fibrosis.
| S-EPMC10212923 | biostudies-literature
Project description:Renal tubulointerstitial fibrosis is the pathological feature of AAN. Aristolochic acid nephropathy (AAN)was induced by a one-time intraperitoneal injection of aristolochic acid in PBS. By RNA sequencing analysis in AAN mice, we observed the significant changes of genes important in regulating cell cycle.
2022-11-10 | GSE217176 | GEO
Project description:Numb is a multifunctional protein involved in diverse cellular processes. However, the function of Numb in kidney remains unclear. Here, we reported that Numb is expressed in renal tubules and glomeruli in normal adult kidney. Numb expression was upregulated in fibrotic kidneys induced by unilateral ureteral obstruction (UUO) in mice as well as in human fibrotic kidney tissues. Numb overexpression in cultured proximal tubular cells increased the G2/M cell population and upregulated the expression of TGF-β1 and CTGF. Whereas, proximal tubule Numb knockout (PEPCK-Numb-KO) mice showed reduced G2/M arrest, decreased expression of TGF-β1 and CTGF, and attenuated fibrotic lesions due to either UUO or unilateral ischemia reperfusion nephropathy. Inhibiting p53 activity by pifithrin-` dramatically mitigated Numb-induced G2/M arrest, indicating that Numb potentiates G2/M arrest via stabilizing p53 protein. Together, these data suggest that Numb is a potential target for anti-fibrosis therapy.
| S-EPMC5041930 | biostudies-literature
Project description:Epithelial cells arrested in G2/M phase of the cell cycle after injury is a key checkpoint for determining the wound-healing to either normal cell proliferation or fibrosis. The mechanism that regulates the fibrogenic response after injury is not well understood. Here, we identified a kidney- and liver-enriched circular RNA, circBNC2, which was abundantly expressed in normal renal tubular cells and hepatocytes but significantly downregulated after acute ischemic or toxic insults. The loss of circBNC2 was at least partially mediated by upregulation of DHX9. Gain-of- and loss-of-function studies, both in vitro and in vivo, demonstrated that circBNC2 acted as a negative regulator for cell G2/M arrest by encoding a novel protein that promoted formation of CDK1/cyclin B1 complex. Restoring circBNC2 in experimentally-induced fibrotic kidney and liver decreased G2/M arrested cells with secretion of fibrotic factors, mitigated extracellular matrix deposition and fibrosis. Decreased expression of circBNC2 and increasement of G2/M arrest of epithelial cells were recapitulated in human IRI-induced chronic kidney disease and inflammation-induced liver fibrosis, highlighting the clinical relevance. These findings suggest that preventing the fibrogenic response by regulating cell cycle arrest might be a potential therapeutic strategy for organ fibrosis.
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Project description:Muscle denervation due to injury, disease or aging results in impaired motor function. Restoring neuromuscular communication requires axonal regrowth and regeneration of neuromuscular synapses. Muscle activity inhibits neuromuscular synapse regeneration. The mechanism by which muscle activity regulates regeneration of synapses is poorly understood. Dach2 and Hdac9 are activity-regulated transcriptional co-repressors that are highly expressed in innervated muscle and suppressed following muscle denervation. Here, we report that Dach2 and Hdac9 inhibit regeneration of neuromuscular synapses. Importantly, we identified Myog and Gdf5 as muscle-specific Dach2/Hdac9-regulated genes that stimulate neuromuscular regeneration in denervated muscle. Interestingly, Gdf5 also stimulates presynaptic differentiation and inhibits branching of regenerating neurons. Finally, we found that Dach2 and Hdac9 suppress miR206 expression, a microRNA involved in enhancing neuromuscular regeneration. RNAseq on innervated and 3 day denervated adult soleus muscle from wildtype mice is compared with that from 3 day denervated soleus muscle from Dach2/Hdac9 deleted mice to identify Dach2/Hdac9-regulated genes.
2015-10-29 | E-GEOD-58669 | biostudies-arrayexpress
Project description:Fibrosis is responsible for chronic progressive kidney failure, which is present in a large number of adults in the developed world. It is increasingly appreciated that acute kidney injury (AKI), resulting in aberrant incomplete repair, is a major contributor to chronic fibrotic kidney disease. The mechanism that triggers the fibrogenic response after injury is not well understood. In ischemic, toxic and obstructive models of AKI, we demonstrate a causal association between epithelial cell cycle G2/M arrest and a fibrotic outcome. G2/M-arrested proximal tubular cells activate c-jun NH(2)-terminal kinase (JNK) signaling, which acts to upregulate profibrotic cytokine production. Treatment with a JNK inhibitor, or bypassing the G2/M arrest by administration of a p53 inhibitor or the removal of the contralateral kidney, rescues fibrosis in the unilateral ischemic injured kidney. Hence, epithelial cell cycle arrest at G2/M and its subsequent downstream signaling are hitherto unrecognized therapeutic targets for the prevention of fibrosis and interruption of the accelerated progression of kidney disease.
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Project description:To understand the underlying molecular mechanism of Hdac9-mediated inflammasome activation and motivated by the molecular scaffolding function of HDAC9, we pursued the hypothesis that HDAC9 may serve as a docking site for cytosolic inflammasome components thereby facilitating its rapid formation upon stimulation. We tested this by performing co-immunoprecipitation experiments coupled with mass spectrometry to assess subunits of the inflammasome that interact with HDAC9.
2025-07-10 | PXD042078 | Pride
Project description:To investigate the role of HDAC9 in innate immnue, we measured the gene expression profile in HDAC9-knockdown macrophages in the absence of innate stimuli by gene-chip in order to find wherther HDAC9 knockdown affect the innate immune factor. We found knockdown of HDAC9 barely affected transcription of innate immnue signaling transducers. HDAC9, as a class IIa HDAC, shuttle between the nucleus and cytoplasm. Here we showed that high expression of cytoplasmic HDAC9, maybe play a Post-translational regulation role in macrophages.
2016-11-06 | GSE74749 | GEO
Project description:Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.
2016-11-17 | GSE89954 | GEO
Project description:Kidney fibrosis results in progressive loss of function, ultimately leading to kidney failure, for which there are limited effective therapeutic strategies. The transcription factor, Forkhead box P2 (Foxp2), has been implicated in organ development and tumorigenesis through its association with the epithelial-to-mesenchymal transition (EMT) process. In this study, we uncovered a novel role of Foxp2 in kidney fibrosis. Expression of Foxp2 was upregulated in kidney tubules from both human chronic glomerulonephritides and animal models of chronic kidney disease. In vitro, Foxp2 was induced in tubular epithelial cells via TGF-β/Smad3 signaling while knockdown of Foxp2 suppressed TGF-β-induced EMT and accumulation of extracellular matrix proteins. In vivo, tubule-specific deletion of Foxp2 attenuated kidney inflammation and tubulointerstitial fibrosis in murine unilateral ureteral obstruction and unilateral ischemic-reperfusion models of progressive CKD, which were accompanied by reduction in cell cycle arrest. Mechanistically, overexpression of Foxp2 inhibited tubular cell proliferation with induction of G2/M cell cycle arrest. Using chromatin-immunoprecipitation sequencing, we identified Foxp2 target genes that are enriched in PI3K/Akt and TGF-β signaling pathways, and further revealed that Foxp2 directly regulated the transcriptional activities of collagen-1, E-cadherin and p21 that are involved in EMT and cell cycle arrest, thereby promoting the profibrotic process. Collectively, our findings provide novel evidence that Foxp2 regulates TGF-β-induced EMT and cell cycle arrest, the key signaling pathways of kidney fibrosis, and suggest that Foxp2 may be a potential therapeutic target for kidney fibrosis.
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