The miR-590/Acvr2a/Terf1 Axis Regulates Telomere Elongation and Pluripotency of Mouse iPSCs.
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ABSTRACT:
SUBMITTER: Liu Q
PROVIDER: S-EPMC6066996 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Embryonic stem cells (ESCs) enable rapid proliferation that also causes DNA damage. To maintain genomic stabilization during rapid proliferation, ESCs must have an efficient system to repress genotoxic stress. Here, we show that withdrawal of leukemia inhibitory factor (LIF), which maintains the self-renewal capability of mouse ESCs (mESCs), significantly inhibits the cell proliferation and DNA damage of mESCs and upregulates the expression of miR-590. miR-590 promotes single-strand break (SSB) and double-strand break (DSB) damage repair, thus slowing proliferation of mESCs without influencing stemness. miR-590 directly targets Activin receptor type 2a (Acvr2a) to mediate Activin signaling. We identified the homologous recombination-mediated repair (HRR) gene, Rad51b, as a downstream molecule of the miR-590/Acvr2a pathway regulating the SSB and DSB damage repair and cell cycle. Our study shows that a miR-590/Acvr2a/Rad51b signaling axis ensures the stabilization of mESCs by balancing DNA damage repair and rapid proliferation during self-renewal.
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Project description:MicroRNAs (miRNAs) are post-transcriptional modulators of gene expression and play an important role in reprogramming process; however, relatively little is known about the underlying regulatory mechanism of miRNAs on how they epigenetically modulate reprogramming and pluripotency. Here, we report that the expression level of microRNA-134 (miR-134) was low in mouse embryonic stem cells (mESCs) but significantly up-regulated during neural differentiation, while down-regulated during the induction of induced pluripotent stem cells (iPSCs) from neural progenitor cells (NPCs). Inhibition of miR-134 by miR-134 sponge promoted the efficiency of reprogramming which also was highly similar to mESCs. On the contrary, up-regulation of miR-134 repressed iPSCs induction. We also found that inhibition of miR-134 promoted the maturation of pre-iPSCs and increased its pluripotency. We also showed that miR-134 can directly target to the pluripotency related factor Methyl-CpG-binding domain protein 3 (Mdb3) 3' untranslated regions (3' UTR) to down-regulate its expression. And Mbd3 was found to promote the induction of iPSCs and could block the repression of reprogramming caused by overexpression of miR-134. This work revealed the critical function of miR-134-Mbd3 axis on regulating reprogramming and pluripotency of iPSCs derived from the NPCs, and might provide an insight into the miR-134-Mbd3 axis on regulating the iPSCs quality for further clinical treatment.
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Project description:Critically short telomeres activate p53-mediated apoptosis, resulting in organ failure and leading to malignant transformation. Mutations in genes responsible for telomere maintenance are linked to a number of human diseases. We derived induced pluripotent stem cells (iPSCs) from 4 patients with aplastic anemia or hypocellular bone marrow carrying heterozygous mutations in the telomerase reverse transcriptase (TERT) or the telomerase RNA component (TERC) telomerase genes. Both mutant and control iPSCs upregulated TERT and TERC expression compared with parental fibroblasts, but mutant iPSCs elongated telomeres at a lower rate compared with healthy iPSCs, and the deficit correlated with the mutations' impact on telomerase activity. There was no evidence for alternative lengthening of telomere (ALT) pathway activation. Elongation varied among iPSC clones derived from the same patient and among clones from siblings harboring identical mutations. Clonal heterogeneity was linked to genetic and environmental factors, but was not influenced by residual expression of reprogramming transgenes. Hypoxia increased telomere extension in both mutant and normal iPSCs. Additionally, telomerase-mutant iPSCs showed defective hematopoietic differentiation in vitro, mirroring the clinical phenotype observed in patients and demonstrating that human telomere diseases can be modeled utilizing iPSCs. Our data support the necessity of studying multiple clones when using iPSCs to model disease.
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Project description:BackgroundCircular RNAs (circRNAs) have been considered to mediate occurrence and development of human cancers, generally acting as microRNA (miRNA) sponges to regulate downstream genes expression. However, the aberrant expression profile and dysfunction of circRNAs in human bladder cancer remain to be investigated. The present study aims to elucidate the potential role and molecular mechanism of circACVR2A in regulating the proliferation and metastasis of bladder cancer.MethodscircACVR2A (hsa_circ_0001073) was identified by RNA-sequencing and validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. The role of circACVR2A in bladder cancer was assessed both in vitro and in vivo. Biotin-coupled probe pull down assay, biotin-coupled microRNA capture, dual-luciferase reporter assay, and fluorescence in situ hybridization were conducted to evaluate the interaction between circACVR2A and microRNAs.ResultsThe expression of circACVR2A was lower in bladder cancer tissues and cell lines. The down-regulation of circACVR2A was positively correlated with aggressive clinicopathological characteristics, and circACVR2A served as an independent risk factor for overall survival in bladder cancer patients after cystectomy. Our in vivo and in vitro data indicated that circACVR2A suppressed the proliferation, migration and invasion of bladder cancer cells. Mechanistically, we found that circACVR2A could directly interact with miR-626 and act as a miRNA sponge to regulate EYA4 expression.ConclusionscircACVR2A functions as a tumor suppressor to inhibit bladder cancer cell proliferation and metastasis through miR-626/EYA4 axis, suggesting that circACVR2A is a potential prognostic biomarker and therapeutic target for bladder cancer.
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Project description:Accumulating evidences indicate that 3'UTR of the coding gene can act as crucial regulators in gastric cancer (GC). However, the detailed mechanisms and responsive targets are not well established. Here, we found that acvr1b gene 3'UTR (acv3UTR) was elevated in GC tissue, the expression of which was significantly correlated with advanced pTNM-stage and poor outcome in clinical patients. Forced expression of acv3UTR promoted GC cells growth in vitro and in vivo. Mechanistically, our results suggested that acv3UTR functioned as an oncogenic competing endogenous RNA via sponging miR-590-5p and enhancing YAP1 level. Tumor suppressor miR-590-5p was a molecular module in acv3UTR regulatory axis, the forced expression of which led to impairing of oncogenic potential of acv3UTR. The positive correlation of acv3UTR and YAP1 expression, and the negative correlation of acv3UTR and miR-590-5p expression, were verified in GC patients. Moreover, CFIm25 was identified as a key regulator contributing to acv3UTR aberrant expression in GC binding to UGUA-264 motif. Overall, our finding defines a mechanism for understanding the potential role of acv3UTR transcription in GC tumorigenesis, and indicates a correlation between 3'UTR trans-regulatory effect and GC development.
| S-EPMC7142022 | biostudies-literature
Project description:Multiple myeloma (MM) is a blood disease characterized by the malignant accumulation of monoclonal plasma cells in the bone marrow. Among the pathological consequences of the MM, defects in osteogenesis characterized by osteolytic lesions, osteopenia, and pathologic fractures are frequently described. Che-1/AATF (Che-1) is a co-transcriptional factor involved in MM transformation and proliferation. Here, we show that Che-1 expression in MM contributes to maintaining low level of WWTR1 (TAZ), a transcriptional coactivator downstream of the Hippo-signaling pathway. We report that the miR-590-3p, deriving from the mRNA splicing of the EIF4H host gene, can target TAZ, contributing to downregulating its expression in MM. Furthermore, we demonstrate by in vivo and in vitro experiments that Che-1 transcriptionally induces EIF4H gene. We provide data to support that miR-590-3p is secreted by MM cells in vitro and in vivo and that can inhibit TAZ levels and the physiological transcriptional expression of osteogenic-related genes, in mesenchymal stem cells. Our findings unveil an unexplored novel Che-1/miR-590-3p/TAZ axis in MM tumorigenesis by providing a rationale to explore the therapeutic potential of metastatic bone lesions.
2024-04-10 | GSE234642 | GEO
Project description:BACKGROUND:Breast cancer is one of the leading causes of death in women worldwide. Fast growth is the important character of breast cancer, which makes sure the subsequent metastasize and invasion breast cancer. Golgi related genes GOLPH3 has been reported to regulate many kinds of cancers proliferation. However, its upregulator remains largely unknown. miRNA modulate gene expression by post-transcriptional repression to participate in many signaling pathway of breast cancer cell proliferation. miR-590 has been reported to regulate tumorgenesis and could be regulated by its own target ATF-3. But whether miR-590 can be the modulator of Golgi related genes to regulate the breast cancer proliferation is unclear. METHODS:We performed the bioinformatics analysis of survival rate and expression differences of patients using the data of The Cancer Genome Atlas (TCGA).Both of MTS and BrdU assays were used for cell proliferation analysis. Cell cycle was detected by flow cytometry .qRT-PCR was used for detecting the cell cycle related gene expression. Student's t-test or One way anova was used for statistics. RESULTS:We found the upregulation of GOLPH3 in breast cancer samples compared with normal breast tissues, which also was related to the poor prognosis. Overexpression of GOLPH3 significantly promoted proliferation both of MDA-MB-231 cells (ER negative) and MCF-7 cells (ER positive). We further found that miRNA-590-3p could directly target the 3'-UTR of GOLPH3 mRNA to repress its expression. Overexpression of miR-590-3p inhibited the proliferation of MDA-MB-231 and MCF-7 cells. The rescue experiments indicated that overexpression of GOLPH3 significantly resorted the proliferation inhibited by miR-590-3p. We also found that ATF-3 repressed miR-590-3p expression to modulate miR-590/GOLPH3 pathway to regulate breast cancer cells proliferation. CONCLUSIONS:This study not only suggests that the ATF-3/miR-590/GOLPH3 signaling pathway is critically involved in the proliferation of breast cancer cells, but provides a novel therapeutic target and new insight base on epigenetic regulation for future breast cancer diagnosis and clinical treatment.
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Project description:MicroRNAs (miRNAs) are recognized as important regulators of cardiac development, hypertrophy and fibrosis. Recent studies have demonstrated that genetic variations which cause alterations in miRNA:target interactions can lead to disease. We hypothesized that genetic variations in miRNAs that regulate cardiac hypertrophy/fibrosis might be involved in generation of the cardiac phenotype in patients diagnosed with hypertrophic cardiomyopathy (HCM). To investigate this question, we Sanger sequenced 18 miRNA genes previously implicated in myocyte hypertrophy/fibrosis and apoptosis, using genomic DNA isolated from the leukocytes of 199 HCM patients. We identified a single nucleotide polymorphism (rs6971711, C57T SNP) at the 17th position of mature miR-590-3p (= 57th position of pre-miR-590) that is common in individuals of African ancestry. SNP frequency was higher in African American HCM patients (n = 55) than ethnically-matched controls (n = 100), but the difference was not statistically significant (8.2% vs. 6.5%; p = 0.5). Using a cell culture system, we discovered that presence of this SNP resulted in markedly lower levels of mature miR-590-5p (39 ± 16%, p<0.003) and miR-590-3p (20 ± 2%, p<0.003), when compared with wild-type (WT) miR-590, without affecting levels of pri-miR-590 and pre-miR-590. Consistent with this finding, the SNP resulted in reduced target suppression when compared to WT miR-590 (71% suppression by WT vs 60% suppression by SNP, p<0.03). Since miR-590 can regulate TGF-?, Activin A and Akt signaling, SNP-induced reduction in miR-590 biogenesis could influence cardiac phenotype by de-repression of these signaling pathways. Since the SNP is only present in African Americans, population studies in this patient population would be valuable to investigate effects of this SNP on myocyte function and cardiac physiology.
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Project description:Exceptional genomic stability is one of the hallmarks of mouse embryonic stem (ES) cells. However, the genes contributing to this stability remain obscure. We previously identified Zscan4 as a specific marker for two-cell embryo and ES cells. Here we show that Zscan4 is involved in telomere maintenance and long-term genomic stability in ES cells. Only 5% of ES cells express Zscan4 at a given time, but nearly all ES cells activate Zscan4 at least once during nine passages. The transient Zscan4-positive state is associated with rapid telomere extension by telomere recombination and upregulation of meiosis-specific homologous recombination genes, which encode proteins that are colocalized with ZSCAN4 on telomeres. Furthermore, Zscan4 knockdown shortens telomeres, increases karyotype abnormalities and spontaneous sister chromatid exchange, and slows down cell proliferation until reaching crisis by passage eight. Together, our data show a unique mode of genome maintenance in ES cells.
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