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Transcription factor?microRNA synergistic regulatory network revealing the mechanism of polycystic ovary syndrome.

ABSTRACT: Polycystic ovary syndrome (PCOS) is the most common type of endocrine disorder, affecting 5?11% of women of reproductive age worldwide. Transcription factors (TFs) and microRNAs are considered to have crucial roles in the developmental process of several diseases and have synergistic regulatory actions. However, the effects of TFs and microRNAs, and the patterns of their cooperation in the synergistic regulatory network of PCOS, remain to be elucidated. The present study aimed to determine the possible mechanism of PCOS, based on a TF?microRNA synergistic regulatory network. Initially, the differentially expressed genes (DEGs) in PCOS were identified using microarray data of the GSE34526 dataset. Subsequently, the TFs and microRNAs which regulated the DEGs of PCOS were identified, and a PCOS?associated TF?microRNA synergistic regulatory network was constructed. This network included 195 DEGs, 136 TFs and 283 microRNAs, and the DEGs were regulated by TFs and microRNAs. Based on topological and functional enrichment analyses, SP1, mir?355?5p and JUN were identified as potentially crucial regulators in the development of PCOS and in characterizing the regulatory mechanism. In conclusion, the TF?microRNA synergistic regulatory network constructed in the present study provides novel insight on the molecular mechanism of PCOS in the form of synergistic regulated model.

SUBMITTER: Liu HY

PROVIDER: S-EPMC4838149 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Transcription factor‑microRNA synergistic regulatory network revealing the mechanism of polycystic ovary syndrome.

Liu Hai-Ying HY Huang Yu-Ling YL Liu Jian-Qiao JQ Huang Qing Q

Molecular medicine reports 20160321 5

Polycystic ovary syndrome (PCOS) is the most common type of endocrine disorder, affecting 5‑11% of women of reproductive age worldwide. Transcription factors (TFs) and microRNAs are considered to have crucial roles in the developmental process of several diseases and have synergistic regulatory actions. However, the effects of TFs and microRNAs, and the patterns of their cooperation in the synergistic regulatory network of PCOS, remain to be elucidated. The present study aimed to determine the p ...[more]

PMID: 27035648

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Project description:Background Polycystic ovary syndrome (PCOS) is a common multifactorial metabolic and endocrine disorder in women of reproductive age. Increasingly, evidence indicates that the microRNA (miRNA)-mRNA axis contributes to the development of PCOS. Methods To investigate the molecular mechanisms through which miRNA-mRNA expression affects hyperandrogenism, ovarian tissue samples from prenatally androgenized (PNA) mice were subjected to miRNA-seq and RNA-seq analysis. Analyses were performed to identify differentially expressed microRNAs (DEmiRs) and differentially expressed genes (DEGs). In combination with our previous data obtained from clinical samples, we have performed an integrated miRNA-mRNA analysis of PNA mice and granulosa cells (GCs) from patients with PCOS. The changes in expression were validated by RT-qPCR in more mouse models and clinical samples. Results In total, 3,432 genes and 16 miRNAs were differentially expressed in PNA mice compared with the control mice. We investigated the regulation pattern of miRNAs-mRNAs and observed a total of 12 miRNA-mRNA pairs involved in negative regulation. Functional analysis concentrated on insulin resistance, the T cell receptor signaling pathway, and other inflammation-related pathways. Verification of these results by RT-qPCR showed that the expression of miR-106-5p and miR-155-5p in clinical GCs was consistent with that in PNA mice. After predicting the target genes of miR-106-5p and miR-155-5p and performing negative regulation analysis, six target genes were obtained in GCs. The integration analysis showed that the network of miR-106-5p/miR-155-5p targets was mostly concentrated in pathway related to insulin resistance and inflammation. In addition, the upregulation of the inflammatory genes Il18/IL18 and Socs3/SOCS3 was validated in the PNA mice and GCs from patients compared with the appropriate control sample. The in vitro experiments showed that the regulatory relationship observed may be related to the direct stimulation of DHT. Conclusions Our results showed that the miRNA-mRNA regulatory network in PCOS was associated with markers of insulin sensitivity and inflammation. Our study provides a new genetic basis and novel insight regarding the pathogenesis of PCOS.

Project description:BackgroundZishen Yutai Pills (ZSYTP) is a prescription based on traditional Chinese medicine used to treat kidney-deficient pattern in traditional Chinese medicine. It is also widely used clinically for the treatment of polycystic ovary syndrome (PCOS) with positive results. This study aims to explore the potential pharmacological mechanism of ZSYTP for the treatment of PCOS by a network pharmacology approach.MethodsCompounds were collected from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine and TCM Database@ Taiwan, and the corresponding targets were retrieved from PubChem, Swiss Target Prediction, STITCH, and DrugBank. Meanwhile, PCOS targets were retrieved from the GeneCards database, the Online Mendelian Inheritance in Man database, National Center for Biotechnology Information Database, and DrugBank. Subsequently, multiple network construction and gene enrichment analyses were conducted with Cytoscape 3.8.2 software. Based on the previous results in the study, molecular docking simulations were done.Results205 active compounds and 478 ZSYTP target genes were obtained after screening by ADME consideration. 1881 disease-related targets were obtained after removing duplicates. 148 intersection target genes between drug and disease targets were isolated. Gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes analysis highlighted multiple gene functions and different signaling pathways to treat PCOS. Further molecular docking demonstrated the practicality of in vivo action of ZSYTP to a certain extent.ConclusionsIt is possible that the pharmacological effect of ZSYTP on PCOS is linked to the hypoxia-inducible factor 1 (HIF-1) signaling pathway, improving insulin resistance, the variation on gene expression such as RNA splicing, and regulation of mRNA metabolic process. This study paves the way for further research investigating its mechanisms.

Project description:Polycystic ovary syndrome (PCOS) has a largely unknown etiology and presents with a clinical heterogeneous patient group. Small noncoding microRNA (miRNA) might prove promising as biomarker candidates for PCOS patient stratification. Altered miRNA expression profiles have been observed in few studies.The aim was to assess the miRNA expression profile in follicular fluid from PCOS patients and healthy, regularly cycling, matched controls.Experimental case-control study including 49 PCOS women (19 of which were hyperandrogenic and 30 normo-androgenic) and 21 healthy matched women all undergoing in vitro fertilization treatment.Anthropometric and relevant clinical baseline measurements were obtained. Relative expression of miRNA levels were estimated using miRNA quantitative PCR arrays and validated by quantitative RT-PCR. Correlation between miRNAs and clinical relevant measurements was estimated.PCOS women, both normo-androgenic and hyperandrogenic, had decreased levels of miR-24-3p, -29a, -151-3p, and -574-3p compared with controls. Furthermore, miR-518f-3p was differentially expressed within the PCOS group with high levels observed in the hyperandrogenic group compared with the normo-androgenic PCOS patients. Serum levels of total and free T were positively correlated with miR-518f-3p in PCOS subjects (P = .001). Distinction between PCOS and controls could be made using miR-151-3p alone with an area under the curve of 0.91 or a combination of four selected miRNAs (area under the curve, 0.93). Bioinformatic target analysis points to an involvement of these miRNAs in biological pathways involving regulation of cell proliferation, extracellular matrix, and processes in intermediary metabolism.Our study provides evidence that the miRNA expression profile in follicular fluid is altered in PCOS and indicates that specific follicular fluid miRNAs are associated with phenotypical traits of PCOS. An altered miRNA profile holds potentials for new methods of PCOS patient stratification and may contribute to and in part explain the heterogeneous nature found within PCOS women.

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Transcription factor?microRNA synergistic regulatory network revealing the mechanism of polycystic ovary syndrome.

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Transcription factor‑microRNA synergistic regulatory network revealing the mechanism of polycystic ovary syndrome.

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