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Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance.

ABSTRACT: Inheritance of the callipyge phenotype in sheep is an example of polar overdominance inheritance, an unusual mode of inheritance. To investigate the underlying molecular mechanism, we profiled the expression of the genes located in the Delta-like 1 homolog (Dlk1)-type III iodothyronine deiodinase (Dio3) imprinting region in mice. We found that the transcripts of the microRNA (miR) 379/miR-544 cluster were highly expressed in neonatal muscle and paralleled the expression of the Dlk1. We then determined the in vivo role of the miR-379/miR-544 cluster by establishing a mouse line in which the cluster was ablated. The maternal heterozygotes of young mutant mice displayed a hypertrophic tibialis anterior muscle, extensor digitorum longus muscle, gastrocnemius muscle, and gluteus maximus muscle and elevated expression of the DLK1 protein. Reduced expression of DLK1 was mediated by miR-329, a member of this cluster. Our results suggest that maternal expression of the imprinted miR-379/miR-544 cluster regulates paternal expression of the Dlk1 gene in mice. We therefore propose a miR-based molecular working model for polar overdominance inheritance.

SUBMITTER: Gao YQ

PROVIDER: S-EPMC4640741 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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Project description:Chronic obstructive pulmonary disease (COPD) has become a significant public health risk. Long non-coding RNAs (lncRNAs) have been identified as important factors involved in the proliferation, apoptosis and inflammatory cytokine expression of lung cells. Peripheral blood samples from 66 subjects (18 non-smokers, 24 smokers without COPD and 28 smokers with COPD) and HBE135-E6E7 cell treated with cigarette smoke extract (CSE) or not were used as the research object. The aim of the present study was to investigate the underlying mechanism of lncRNA maternally expressed gene 3 (MEG3) in COPD. Following transfection with microRNA (miR)-149-3p mimics, miR-negative control mimics, miR-149-3p inhibitor, miR-negative control inhibitor, small interfering (si)RNA targeting MEG3 (si-MEG3) and si-negative control (si-NC), levels of MEG3 and microRNA (miR)-149-3p were detected using reverse transcription-quantitative PCR, Proliferation and apoptosis were examined using the Cell Counting Kit-8 and flow cytometry assays, respectively. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Protein levels of B-cell lymphoma-2 (Bcl-2), cleaved-caspase-3, cleaved-caspase-9, phosphorylated (p)-p65, total (t)-p65, p-lkBα and t-lkBα were measured by western blotting. Luciferase assay was conducted to examine the relationship between MEG3 and miR-149-3p. LncRNA MEG3 was highly expressed, whereas miR-149-3p expression was downregulated in smokers with COPD peripheral blood samples, compared with non-smokers and smokers without COPD samples. Compared with untreated human bronchial epithelial (HBE) cells, MEG3 expression was increased in cigarette smoke extract (CSE)-treated HBE cells. Compared with CSE-treated HBE cells transfected with si-NC, MEG3 knockdown promoted cell proliferation and inhibited apoptosis in CSE-treated HBE cells transfected with si-MEG3, and it also decreased the levels of IL-6, TNF-α, Bcl-2 and increased cleaved-caspase-3 and cleaved-caspase-9 in CSE-treated HBE cells transfected with si-MEG3. The luciferase assay demonstrated that miR-149-3p has target sites for MEG3. MEG3 was demonstrated to regulate the NF-κB signaling pathway by sponging miR-149-3p in CSE-treated HBE cells. In conclusion, these findings suggested that MEG3 promoted proliferation and inhibited apoptosis by regulating the NF-κB signal pathway via miR-149-3p in CSE-treated HBE cells. These results provide an insight for further verification and understanding of the molecular basis of COPD.

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Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance.

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