MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2.
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ABSTRACT:
SUBMITTER: Fuentes-Mattei E
PROVIDER: S-EPMC10967479 | biostudies-literature | 2024 Feb
REPOSITORIES: biostudies-literature
Publications
miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2.
Fuentes-Mattei Enrique E Bayraktar Recep R Manshouri Taghi T Silva Andreia M AM Ivan Cristina C Gulei Diana D Fabris Linda L Soares do Amaral Nayra N Mur Pilar P Perez Cristina C Torres-Claudio Elizabeth E Dragomir Mihnea P MP Badillo-Perez Adriana A Knutsen Erik E Narayanan Pranav P Golfman Leonard L Shimizu Masayoshi M Zhang Xinna X Zhao Wanke W Ho Wanting Tina WT Estecio Marcos Roberto MR Bartholomeusz Geoffrey G Tomuleasa Ciprian C Berindan-Neagoe Ioana I Zweidler-McKay Patrick A PA Estrov Zeev Z Zhao Zhizhuang J ZJ Verstovsek Srdan S Calin George A GA Redis Roxana S RS
JCI insight 20240208 3
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Project description:Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAKV617F mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK2V617F inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-543 was significantly upregulated in nonresponders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2V617F mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-18 | GSE142240 | GEO
Project description:We analyzed 14 patients with Myelofibrosis (MF) to determine the miRNA profile of patients not responding to current MF treatment. We used Affymetrix miRNA-3 array to profile the differentially expressed miRNA in bone-marrow between patients with MF that respond to current MF treatment and the patients with MF that do not respond to current MF treatment.
2019-12-18 | GSE142239 | GEO
Project description:We analyzed mK562 cells with miR-543 overexpressed or empty vector to determine the mRNA profile of miR-543 overexpressed K562 cells. We used Affymetrix Clariom S Human Array to profile the differentially expressed mRNA in miR-543 overexpressed and control cells
2019-12-18 | GSE142236 | GEO
Project description:MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2
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Project description:MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2 [mRNA]
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Project description:MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2 [miRNA]
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Project description:BackgroundDiabetic nephropathy (DN) is one of the most common and serious complications of diabetes, which can lead to renal failure and fatality. miRNAs are an important class of endogenous non-coding RNAs implicated in a wide range of biological processes and pathological conditions. This study aims to investigate the potential functional roles of miR-543 in DN and its underlying mechanisms.MethodsqRT-PCR was performed to detect the expression levels of miR-543 and TSPAN8 in kidney tissues of mice with DN. Western blot (WB) was used to measure the protein levels. CCK8 assay was employed to evaluate the proliferation of HK2 cells. Dual luciferase reporter assay was conducted to verify the functional interaction between miR-543 and TSpan8.ResultsThe downregulation of miR-543 and upregulation of TSPAN8 were observed in kidney tissues of mice with DN. miR-543 mimic significantly decreased cell proliferation and autophagy in high-glucose (HG)-induced HK2 cells, and promoted cell fibrosis. We further identified a putative binding site between miR-543 and TSPAN8, which was validated by Dual luciferase reporter assay. The treatment of miR-543 mimic and miR-543 inhibitor could reduce or increase TSPAN8 protein level respectively. We further showed that the overexpression of TSPAN8 could attenuate HG-induced cell injury by reducing fibrosis and increase autophagy. The effects of miR-543 mimic in proliferation, fibrosis, and autophagy were rescued by TSPAN8 overexpression.ConclusionsOur study indicate that miR-543 mediates high-glucose induced DN via targeting TSPAN8. Interfering miR-543/TSPAN8 axis could serve as potential approach to ameliorate DN.
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Project description:Tet enzymes (Tet1/2/3) convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in various embryonic and adult tissues. Mice mutant for either Tet1 or Tet2 are viable, raising the question of whether these enzymes have overlapping roles in development. Here we have generated Tet1 and Tet2 double-knockout (DKO) embryonic stem cells (ESCs) and mice. DKO ESCs remained pluripotent but were depleted of 5hmC and caused developmental defects in chimeric embryos. While a fraction of double-mutant embryos exhibited midgestation abnormalities with perinatal lethality, viable and overtly normal Tet1/Tet2-deficient mice were also obtained. DKO mice had reduced 5hmC and increased 5mC levels and abnormal methylation at various imprinted loci. Nevertheless, animals of both sexes were fertile, with females having smaller ovaries and reduced fertility. Our data show that loss of both enzymes is compatible with development but promotes hypermethylation and compromises imprinting. The data also suggest a significant contribution of Tet3 to hydroxylation of 5mC during development.
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Project description:ObjectiveOvarian cancer (OvCa) is the most lethal gynaecological malignancy worldwide. We aimed to illustrate the potential function and molecular mechanism of exosomal microRNA-543 (miR-543) in the oncogenesis and development of OvCa.MethodsDifferentially expressed microRNAs in exosomes derived from OvCa cell lines were identified by bioinformatic analysis and verified by RT-PCR. Cell proliferation ability was estimated by clonogenic and 5-ethynyl-2'-deoxyuridine assays in vitro and in vivo. Potential involved pathways and targets of exosomal miRNAs were analysed using DIANA and verified by pyrosequencing, glucose quantification, dual-luciferase reporter experiments, and functional rescue assays.ResultsBioinformatic analysis identified miR-543 and its potential target genes involved in the cancer-associated proteoglycan pathway. The expression of miR-543 was significantly decreased in exosomes derived from OvCa cell lines, patient serum, and OvCa tissues, while the mRNA levels of insulin-like growth factor 2 (IGF2) were increased. Furthermore, the overexpression of miR-543 resulted in the suppression of OvCa cell proliferation in vitro and in vivo. Moreover, miR-543 was significantly negatively correlated with IGF2 in OvCa tissues in comparison with paracarcinoma tissues. Notably, upregulation of miR-543 led to increased cell supernatant glucose levels and suppressed cell growth, which was rescued by overexpression of IGF2.ConclusionsExosomal miR-543 participates in the proteoglycan pathway to suppress cell proliferation by targeting IGF2 in OvCa.
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