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Cohort of estrogen-induced microRNAs regulate adrenomedullin expression.

ABSTRACT: Estrogen regulates the expression of many genes and has been correlated with differences in cardiac contraction; however, the underlying mechanisms remain poorly defined. Adrenomedullin (Adm = gene; AM = protein) is a multifunctional peptide with inotropic actions. Previous studies have demonstrated that estrogen enhances the expression of Adm, suggesting a relationship between AM and estrogen in cardiac contraction during physiological and pathological states. In this study, female mice in a mouse model of genetic Adm overexpression, abbreviated as Adm(hi/hi), were found to express 60 times more Adm in the heart than wild-type littermates, compared with the three-fold elevation of Adm previously reported in Adm(hi/hi) male hearts. Thus, this study sought to further investigate any functional consequences of increased cardiac Adm expression and begin exploring the mechanisms that regulate Adm expression in an estrogen-dependent fashion. This study revealed that heart function is enhanced in Adm(hi/hi) females, which along with Adm expression levels, was reversed following ovariectomization. Since the Adm(hi/hi) line was generated by the displacement of the 3' untranslated region (UTR), the native 3'UTR was examined for estrogen-induced microRNAs target sites to potentially explain the aberrant overexpression observed in Adm(hi/hi) female hearts. Using a bioinformatic approach, it was determined that the mouse Adm 3'UTR contains many target sites for previously characterized estrogen-induced microRNAs. This study also determined that the novel microRNA, miR-879, is another estrogen-induced microRNA that interacts with the 3'UTR of Adm to destabilize the mRNA. Together, these studies revealed that estrogen-induced microRNAs are important for balancing cardiac Adm expression in females.

SUBMITTER: Wetzel-Strong SE

PROVIDER: S-EPMC4796641 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Cohort of estrogen-induced microRNAs regulate adrenomedullin expression.

Wetzel-Strong Sarah E SE Li Manyu M Espenschied Scott T ST Caron Kathleen M KM

American journal of physiology. Regulatory, integrative and comparative physiology 20151118 2

Estrogen regulates the expression of many genes and has been correlated with differences in cardiac contraction; however, the underlying mechanisms remain poorly defined. Adrenomedullin (Adm = gene; AM = protein) is a multifunctional peptide with inotropic actions. Previous studies have demonstrated that estrogen enhances the expression of Adm, suggesting a relationship between AM and estrogen in cardiac contraction during physiological and pathological states. In this study, female mice in a mo ...[more]

PMID: 26582637

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Project description:MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate important intracellular biological processes. In myasthenia gravis (MG), a disease-specific pattern of elevated circulating miRNAs has been found, and proposed as potential biomarkers. These elevated miRNAs include miR-150-5p, miR-21-5p, and miR-30e-5p in acetylcholine receptor antibody seropositive (AChR+) MG and miR-151a-3p, miR-423-5p, let-7a-5p, and let-7f-5p in muscle-specific tyrosine kinase antibody seropositive (MuSK+) MG. In this study, we examined the regulation of each of these miRNAs using chromatin immunoprecipitation sequencing (ChIP-seq) data from the Encyclopedia of DNA Elements (ENCODE) to gain insight into the transcription factor pathways that drive their expression in MG. Our aim was to look at the transcription factors that regulate miRNAs and then validate some of those in vivo with cell lines that have sufficient expression of these transcription factors This analysis revealed several transcription factor families that regulate MG-specific miRNAs including the Forkhead box or the FOXO proteins (FoxA1, FoxA2, FoxM1, FoxP2), AP-1, interferon regulatory factors (IRF1, IRF3, IRF4), and signal transducer and activator of transcription proteins (Stat1, Stat3, Stat5a). We also found binding sites for nuclear factor of activated T-cells (NFATC1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), early growth response factor (EGR1), and the estrogen receptor 1 (ESR1). AChR+ MG miRNAs showed a stronger overall regulation by the FOXO transcription factors, and of this group, miR-21-5p, let-7a, and let 7f were found to possess ESR1 binding sites. Using a murine macrophage cell line, we found activation of NF-κB -mediated inflammation by LPS induced expression of miR-21-5p, miR-30e-5p, miR-423-5p, let-7a, and let-7f. Pre-treatment of cells with the anti-inflammatory drugs prednisone or deflazacort attenuated induction of inflammation-induced miRNAs. Interestingly, the activation of inflammation induced packaging of the AChR+-specific miRNAs miR-21-5p and miR-30e-5p into exosomes, suggesting a possible mechanism for the elevation of these miRNAs in MG patient serum. In conclusion, our study summarizes the regulatory transcription factors that drive expression of AChR+ and MuSK+ MG-associated miRNAs. Our findings of elevated miR-21-5p and miR-30e-5p expression in immune cells upon inflammatory stimulation and the suppressive effect of corticosteroids strengthens the putative role of these miRNAs in the MG autoimmune response.

Dataset Information

Cohort of estrogen-induced microRNAs regulate adrenomedullin expression.

Publications

Cohort of estrogen-induced microRNAs regulate adrenomedullin expression.

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