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Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.

ABSTRACT: Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and osteogenic differentiation; however, the mechanism by which miRNA expression is altered during stem cell differentiation is less understood. Here we demonstrate for the first time that adipose-derived stromal/stem cells (ASCs) induced to an adipogenic or osteogenic lineage have differences in strand preference (-3p and -5p) for miRNAs originating from the same primary transcript. Furthermore, evaluation of miRNA expression in ASCs demonstrates alterations in both miRNA strand preference and 5'seed site heterogeneity. Additionally, we show that during stem cell differentiation there are alterations in expression of genes associated with the miRNA biogenesis pathway. Quantitative RT-PCR demonstrated changes in the Argonautes (AGO1-4), Drosha, and Dicer at intervals of ASC adipogenic and osteogenic differentiation compared to untreated ASCs. Specifically, we demonstrated altered expression of the AGOs occurring during both adipogenesis and osteogenesis, with osteogenesis increasing AGO1-4 expression and adipogenesis decreasing AGO1 gene and protein expression. These data demonstrate changes to components of the miRNA biogenesis pathway during stromal/stem cell differentiation. Identifying regulatory mechanisms for miRNA processing during ASC differentiation may lead to novel mechanisms for the manipulation of lineage differentiation of the ASC through the global regulation of miRNA as opposed to singular regulatory mechanisms.

SUBMITTER: Martin EC

PROVIDER: S-EPMC6152510 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.

Martin E C EC Qureshi A T AT Llamas C B CB Burow M E ME King A G AG Lee O C OC Dasa V V Freitas M A MA Forsberg J A JA Elster E A EA Davis T A TA Gimble J M JM

Adipocyte 20180207 2

Stromal/stem cell differentiation is controlled by a vast array of regulatory mechanisms. Included within these are methods of mRNA gene regulation that occur at the level of epigenetic, transcriptional, and/or posttranscriptional modifications. Current studies that evaluate the posttranscriptional regulation of mRNA demonstrate microRNAs (miRNAs) as key mediators of stem cell differentiation through the inhibition of mRNA translation. miRNA expression is enhanced during both adipogenic and oste ...[more]

PMID: 29411671

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Project description:Human adipose tissue‑derived stromal stem cells (HASCs) represent a promising regenerative resource for breast reconstruction and augmentation. However, the mechanisms involved in inducing its adipogenic differentiation remain to be fully elucidated. The present study aimed to comprehensively investigate the expression changes in mRNAs, microRNAs (miRNAs) and long non‑coding (lnc)RNAs during the adipogenic differentiation of HASCs, and screen crucial lncRNA‑miRNA‑mRNA interaction axes using microarray datasets GSE57593, GSE25715 and GSE61302 collected from the Gene Expression Omnibus database. Following pretreatment, differentially expressed genes (DEGs), miRNAs (DE‑miRNAs) or lncRNAs (DE‑lncRNAs) between undifferentiated and differentiated HASCs were identified using the Linear Models for Microarray data method. A protein‑protein interaction (PPI) network was constructed for the DEGs based on protein databases, followed by module analysis. The 'lncRNA‑miRNA‑mRNA' competing endogenous RNA (ceRNA) network was constructed based on the interactions between miRNAs and mRNAs, lncRNAs and miRNAs predicted by the miRWalk and lnCeDB databases. The underlying functions of mRNAs were predicted using the clusterProfiler package. In the present study, 905 DEGs, 36 DE‑miRNAs and 577 DE‑lncRNAs were screened between undifferentiated HASCs and differentiated adipocyte cells. PPI network analysis demonstrated that LEP may be a hub gene, which was also enriched in significant module 5. LEP was predicted to be involved in the Janus kinase‑signal transducer and activator of transcription signaling pathway, and the regulation of inflammatory response. The upregulation of LEP was regulated by downregulated hsa‑miRNA (miR)‑130b‑5p and hsa‑miR‑23a‑5p (or hsa‑miR‑302d‑3p). These miRNAs also respectively interacted with RP11‑552F3.9 (or RP11‑15A1.7), ultimately forming the ceRNA axes. In conclusion, the present study revealed that the RP11‑552F3.9 (RP11‑15A1.7)‑hsa‑miR‑130b‑5p/hsa‑miR‑23a‑5p (hsa‑miR‑302d‑3p)‑LEP interaction axes may be crucial for inducing the adipogenic differentiation of HASCs via involvement in inflammation.

Dataset Information

Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.

Publications

Mirna biogenesis pathway is differentially regulated during adipose derived stromal/stem cell differentiation.

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