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Regulation of behavioral response to stress by microRNA-690.

ABSTRACT: Psychiatric disorders are affected by genetic susceptibility and environmental adversities. Therefore, the regulation of gene expression under certain environments, such as stress, is a key issue in psychiatric disorders. MicroRNAs (miRNAs) have been implicated as post-transcriptional regulators of several biological processes, which can be differentially controlled through the targeting of multiple mRNAs. However, studies reporting the functions of miRNAs in relation to stress are lacking. In this study, we identified a significant increase in the expression of miRNA-690 (miR-690) in the medial prefrontal cortex (mPFC) of FK506-binding protein 51 knock-out (Fkbp5 KO) mice. In addition, the expression pattern of miR-690 was similar to the sucrose preference of the same group in WT and Fkbp5 KO mice. miR-690 was injected into the mPFC using a recombinant adeno-associated virus mediated gene delivery method. After recovery, miR-690 overexpressing mice were exposed to restraint stress for 2 weeks. In the sucrose preference test and forced swim test, the stressed miR-690 overexpressing mice showed higher sucrose preference and lower immobility time, respectively, than stressed mice injected with the control virus. In the novel object recognition test, the stressed miR-690 overexpressing mice interacted longer with the novel object than those injected with the control virus. These results showed that miR-690 might play a role in stress resilience and could provide new insights into the epigenetic regulation of stress-associated biological functions and diseases, such as depression and post-traumatic stress disorder.

SUBMITTER: Park J

PROVIDER: S-EPMC7797085 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Regulation of behavioral response to stress by microRNA-690.

Park Jungyoung J Lee Joonhee J Choi Koeul K Kang Hyo Jung HJ

Molecular brain 20210109 1

Psychiatric disorders are affected by genetic susceptibility and environmental adversities. Therefore, the regulation of gene expression under certain environments, such as stress, is a key issue in psychiatric disorders. MicroRNAs (miRNAs) have been implicated as post-transcriptional regulators of several biological processes, which can be differentially controlled through the targeting of multiple mRNAs. However, studies reporting the functions of miRNAs in relation to stress are lacking. In t ...[more]

PMID: 33422095

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Project description:BackgroundHypoxia is often encountered in solid tumors and known to contribute to aggressive tumor behavior, radiation- and chemotherapy resistance resulting in a poor prognosis for the cancer patient. MicroRNAs (miRNAs) play a role in the regulation of the tumor cell response to hypoxia, however, not much is known about the involvement of miRNAs in hypoxic signalling pathways in soft tissue sarcomas (STS).MethodA panel of twelve STS cell lines was exposed to atmospheric oxygen concentrations (normoxia) or 1% oxygen (hypoxia) for up to 48 h. Hypoxic conditions were verified and miRNA expression profiles were assessed by LNA™ oligonucleotide microarrays and RT-PCR after 24 h. The expression of target genes regulated by hypoxia responsive miRNAs is examined by end-point PCR and validated by luciferase reporter constructs.ResultsExposure of STS cell lines to hypoxic conditions gave rise to upregulation of Hypoxia Inducible Factor (HIF) 1α protein levels and increased mRNA expression of HIF1 target genes CA9 and VEGFA. Deregulation of miRNA expression after 24 h of hypoxia was observed. The most differentially expressed miRNAs (p<0.001) in response to hypoxia were miR-185-3p, miR-485-5p, miR-216a-5p (upregulated) and miR-625-5p (downregulated). The well-known hypoxia responsive miR-210-3p could not be reliably detected by the microarray platform most likely for technical reasons, however, its upregulation upon hypoxic stress was apparent by qPCR. Target prediction algorithms identified 11 potential binding sites for miR-485-5p and a single putative miR-210-3p binding site in the 3'UTR of HIF3α, the least studied member of the HIF family. We showed that HIF3α transcripts, expressing a 3'UTR containing the miR-485-5p and miR-210-3p target sites, are expressed in all sarcoma cell lines and upregulated upon hypoxia. Additionally, luciferase reporter constructs containing the 3'UTR of HIF3α were used to demonstrate regulation of HIF3α by miR-210-3p and miR-485-5p.ConclusionHere we provide evidence for the miRNA mediated regulation of HIF3α by hypoxia responsive miRNAs in STS, which may help to tightly regulate and fine-tune the hypoxic response. This provides a better insight into the mechanisms underlying the hypoxic response in STS and may ultimately yield information on novel prognostic and predictive markers or targets for treatment.

Project description:?(9)-Tetrahydrocannabinol (THC), the major bioactive component of marijuana, has been shown to induce functional myeloid-derived suppressor cells (MDSCs) in vivo. Here, we studied the involvement of microRNA (miRNA) in this process. CD11b(+)Gr-1(+) MDSCs were purified from peritoneal exudates of mice administered with THC and used for genome-wide miRNA profiling. Expression of CD31 and Ki-67 confirmed that the THC-MDSCs were immature and proliferating. THC-induced MDSCs exhibited distinct miRNA expression signature relative to various myeloid cells and BM precursors. We identified 13 differentially expressed (>2-fold) miRNA in THC-MDSCs relative to control BM precursors. In silico target prediction for these miRNA and pathway analysis using multiple bioinformatics tools revealed significant overrepresentation of Gene Ontology clusters within hematopoiesis, myeloid cell differentiation, and regulation categories. Insulin-like growth factor 1 signaling involved in cell growth and proliferation, and myeloid differentiation pathways were among the most significantly enriched canonical pathways. Among the differentially expressed, miRNA-690 was highly overexpressed in THC-MDSCs (?16-fold). Transcription factor CCAAT/enhancer-binding protein ? (C/EBP?) was identified as a potential functional target of miR-690. Supporting this, C/EBP? expression was attenuated in THC-MDSCs as compared with BM precursors and exhibited an inverse relation with miR-690. miR-690 knockdown using peptide nucleic acid-antagomiR was able to unblock and significantly increase C/EBP? expression establishing the functional link. Further, CD11b(+)Ly6G(+)Ly6C(+) and CD11b(+)Ly6G(-)Ly6C(+) purified subtypes showed high levels of miR-690 with attenuated C/EBP? expression. Moreover, EL-4 tumor-elicited MDSCs showed increased miR-690 expression. In conclusion, miRNA are significantly altered during the generation of functional MDSC from BM. Select miRNA such as miR-690 targeting genes involved in myeloid expansion and differentiation likely play crucial roles in this process and therefore in cannabinoid-induced immunosuppression.

Project description:BackgroundThe regulatory mechanism of insulin-producing cells (IPCs) differentiation from induced pluripotent stem cells (iPSCs) in vitro is very important in the phylogenetics of pancreatic islets, the molecular pathogenesis of diabetes, and the acquisition of high-quality pancreatic ?-cells derived from stem cells for cell therapy.MethodsmiPSCs were induced for IPCs differentiation. miRNA microarray assays were performed by using total RNA from our iPCs-derived IPCs containing undifferentiated iPSCs and iPSCs-derived IPCSs at day 4, day 14, and day 21 during step 3 to screen the differentially expressed miRNAs (DEmiRNAs) related to IPCs differentiation, and putative target genes of DEmiRNAs were predicted by bioinformatics analysis. miR-690 was selected for further research, and MPCs were transfected by miR-690-agomir to confirm whether it was involved in the regulation of IPCs differentiation in iPSCs. Quantitative Real-Time PCR (qRT-PCR), Western blotting, and immunostaining assays were performed to examine the pancreatic function of IPCs at mRNA and protein level respectively. Flow cytometry and ELISA were performed to detect differentiation efficiency and insulin content and secretion from iPSCs-derived IPCs in response to stimulation at different concentration of glucose. The targeting of the 3'-untranslated region of Sox9 by miR-690 was examined by luciferase assay.ResultsWe found that miR-690 was expressed dynamically during IPCs differentiation according to the miRNA array results and that overexpression of miR-690 significantly impaired the maturation and insulinogenesis of IPCs derived from iPSCs both in vitro and in vivo. Bioinformatic prediction and mechanistic analysis revealed that miR-690 plays a pivotal role during the differentiation of IPCs by directly targeting the transcription factor sex-determining region Y (SRY)-box9. Furthermore, downstream experiments indicated that miR-690 is likely to act as an inactivated regulator of the Wnt signaling pathway in this process.ConclusionsWe discovered a previously unknown interaction between miR-690 and sox9 but also revealed a new regulatory signaling pathway of the miR-690/Sox9 axis during iPSCs-induced IPCs differentiation.

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Regulation of behavioral response to stress by microRNA-690.

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Regulation of behavioral response to stress by microRNA-690.

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