Overexpression of long noncoding RNA 4933425B07Rik leads to renal hypoplasia by inactivating the Wnt/β-catenin signaling pathway
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ABSTRACT:
PROVIDER: PRJNA874072 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21221246.fastq.gz | Fastqsanger.gz | |||
| SRR21221247.fastq.gz | Fastqsanger.gz | |||
| SRR21221248.fastq.gz | Fastqsanger.gz | |||
| SRR21221249.fastq.gz | Fastqsanger.gz | |||
| SRR21221250.fastq.gz | Fastqsanger.gz |
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Project description:Background Congenital anomalies of the kidney and urinary tract (CAKUT) refer to a diverse group of developmental malformations, which are the leading cause of chronic kidney disease and end-stage renal disease in children. The etiology and pathogenesis of CAKUT are complex. In recent years, the relationship between long noncoding RNAs and renal development and disease has attracted much attention. Our previous study established a long noncoding RNA 4933425B07Rik (Rik) overexpression mouse model by inserting the PB transposon and found that overexpression of Rik led to renal hypoplasia. This study aimed to explore the molecular mechanism of renal hypoplasia induced by Rik overexpression in vitro. Results In this study, by constructing Rik overexpression cell models and a Rik knockout cell model to accompany previously developed RikPB/PB;Hoxb7 mice and by applying RNA-seq, RT‒PCR and other experimental methods, it was found that when Rik was highly expressed, the expression of Wnt10b, Fzd8 and β-catenin decreased, while Rik was knock down, the expression of these genes increased. Conclusions The findings suggest that overexpression of Rik leads to renal hypoplasia by inactivating the Wnt/β-catenin signaling pathway. This research perspective may provide a basis for exploring new causes and mechanisms of CAKUT and provide new targets for the prevention and treatment of CAKUT.
2022-08-30 | GSE212130 | GEO
Project description:Congenital anomalies of the kidney and urinary tract (CAKUT) is a general term for a class of diseases that are mostly caused by intrauterine genetic development limitation. Without timely intervention, certain children with CAKUT may experience progressive decompensation and a rapid decline in renal function, which will ultimately result in end-stage renal disease. At present, a comprehensive understanding of the pathogenic signaling events of CAKUT is lacking. The role of long noncoding RNAs (lncRNAs) in renal development and disease have recently received much interest. In previous research, we discovered that mice overexpressing the lncRNA 4933425B07Rik (Rik) showed a range of CAKUT phenotypes, primarily renal hypoplasia. The current study investigated the molecular basis of renal hypoplasia caused by Rik overexpression. We first used Rapid Amplification of cDNA ends (RACE) to obtain the full-length sequence of Rik in Rik +/+;Hoxb7 mice. Mouse proximal renal tubule epithelial cells (MPTCs) line with Rik overexpression was constructed using lentiviral methods, and mouse metanephric mesenchyme cell line (MK3) with Rik knockout was then constructed by the CRISPR‒Cas9 method. We performed RNA-seq on the Rik-overexpressing cell line to explore possible differentially expressed molecules and pathways. mRNA expression was confirmed by qRT‒PCR. Reduced levels of Wnt10b, Fzd8, and β-catenin were observed when Rik was expressed robustly. On the other hand, these genes were more highly expressed when Rik was knocked out. These results imply that overabundance of Rik might inhibit the Wnt/β-catenin signaling pathway, which may result in renal hypoplasia. In general, such research might help shed light on CAKUT causes and processes and offer guidance for creating new prophylactic and therapeutic strategies.
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Project description:BackgroundDiabetic nephropathy (DN) is one of the principal complications of diabetes and podocyte injury plays an important role in the DN pathogenesis. Wnt/β-catenin signaling overactivation confers podocyte injury and promotes multiple types of renal disease. However, the underlying mechanism of Wnt/β-catenin signaling activation in DN progression has not been fully elucidated. Long noncoding RNA (lncRNA) is a large class of endogenous RNA molecules lacking functional code capacity and which participates in the pathogenesis of human disease, including DN.MethodA diabetes model was constructed by intraperitoneal injection of Streptozotocin in rats. The MPC5 cells were used to create the in vitro model. Western blot and Quantitative reverse-transcriptase-PCR were used to examine the expression of protein and mRNA. The migrated capacity was analyzed by Transwell migration assay. The cell viability was detected by CCK8.ResultsIn the present study, we revealed the association of lncRNA Maternally Expressed Gene 3 (MEG3) with aberrant activation of Wnt/β-catenin signaling and the role of MEG3/Wnt axis in podocyte injury. We found that high glucose (HG) treatment suppressed MEG3 expression in cultured podocytes, activated Wnt/β-catenin signaling and caused podocyte injury as indicated by the downregulation of podocyte-specific markers (podocin and synaptopodin) and the upregulation of snail1 and α-smooth muscle actin. Overexpression of MEG3 attenuated HG-induced podocyte injury by reducing Wnt/β-catenin activity, repressing cell migration, reactive oxygen species production and increasing the viability of podocytes. Furthermore, we provided evidences that restoration of Wnt/β-catenin signaling by specific agonist impeded the protective effect of MEG3 on podocyte injury. Current results demonstrated that MEG3/Wnt axis plays an important role in fostering podocyte injury and may serve as a potential therapeutic target for the treatment of DN.ConclusionlncRNA MEG3 ameliorates podocyte injury in DN via inactivating Wnt/β-catenin signaling.
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Project description:Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of β-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of β-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of β-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between β-catenin and ZNT9, thereby leading to decreased β-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/β-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.
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Project description:To investigate the miR-219-5p decreases the resistance of OC cells to cisplatin via Wnt/β-catenin signaling and autophagy by regulating HMGA2, we tested the A2780 and A2780-DDP cell lines with miRNA-Seq.
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Project description:Wnt/β-catenin signaling is essential for intestinal stem cell homeostasis and aberrant activation of this signaling leads to tumorigenesis. Here we report a function of YTHDF1, an mRNA m6A reader, in mediating β-catenin hyperactivation. Wnt signaling promotes YTHDF1 expression at the translational level. YTHDF1 is dispensable for normal intestinal development in mice while essential for intestinal regeneration. Ythdf1 knockout reduces the stemness of intestinal stem cells, which blocks Wnt-driven tumorigenesis. Genome-wide analysis identifies a subset of Wnt signaling components regulated by YTHDF1 in an m6A-dependent manner. Moreover, we demonstrate that YTHDF1 promotes the translation of TCF7L2/TCF4 to augment β-catenin activation. Targeting YTHDF1 in the established tumors leads to tumor shrinkage and prolonged survival. Together, our studies uncover YTHDF1 as an integral regulator of Wnt signaling at the translational level during intestinal tumorigenesis, which might serve as a promising target for colorectal cancer therapy.
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Project description:Hepatic GS loss leads to increased mTORC1 signaling and ribosome biogenesis in response to β-catenin activation
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Project description:Wnt/beta-catenin signaling is essential for stem cell regulation and cancer formation by activation of target genes transcription. For transcriptional activation, the histone around promoters needs to be modified to remove transcriptional repressors; however, the underlying mechanisms remain largely unknown. Here, we report that Wnt signal erases TCF4-associated H3K9me2/me3 by recruitment of KDM4C through β-catenin to activate gene transcription. In the absence of Wnt3a, PKR phosphorylates KDM4C which induces its ubiquitination and degradation. Wnt3a stabilizes KDM4C through inhibition of GSK3-dependent PKR kinase activity. Stabilized KDM4C accumulates in nucleus. Through interaction with β-catenin, KDM4C binds to and demethylates TCF4-associate Histone H3K9 which leads to HP1 removal and transcription activation. KDM4C-dependent H3K9 demethylation is essential for Wnt-induced gene expression and tumorigenesis. Importantly, KDM4C levels directly correlate with Wnt signaling activation in human glioblastomas. These findings demonstrate a pivotal epigenetic regulation mechanism for Wnt/β-catenin signaling activation in tumorigenesis.
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