Dataset Information

Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBPα.

ABSTRACT: C/EBPα is a critical transcriptional regulator of adipogenesis. How C/EBPα transcription is itself regulated is poorly understood, however, and remains a key question that needs to be addressed for a complete understanding of adipogenic development. Here, we identify a lncRNA, ADINR (adipogenic differentiation induced noncoding RNA), transcribed from a position ∼450 bp upstream of the C/EBPα gene, that orchestrates C/EBPα transcription in vivo. Depletion of ADINR leads to a severe adipogenic defect that is rescued by overexpression of C/EBPα. Moreover, we reveal that ADINR RNA specifically binds to PA1 and recruits MLL3/4 histone methyl-transferase complexes so as to increase H3K4me3 and decrease H3K27me3 histone modification in the C/EBPα locus during adipogenesis. These results show that ADINR plays important roles in regulating the differentiation of human mesenchymal stem cells into adipocytes by modulating C/EBPα in cis.

SUBMITTER: Xiao T

PROVIDER: S-EPMC4649137 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBPα.

Xiao Tengfei T Liu Lihui L Li Hongling H Sun Yu Y Luo Huaxia H Li Tangping T Wang Shihua S Dalton Stephen S Zhao Robert Chunhua RC Chen Runsheng R

Stem cell reports 20151017 5

C/EBPα is a critical transcriptional regulator of adipogenesis. How C/EBPα transcription is itself regulated is poorly understood, however, and remains a key question that needs to be addressed for a complete understanding of adipogenic development. Here, we identify a lncRNA, ADINR (adipogenic differentiation induced noncoding RNA), transcribed from a position ∼450 bp upstream of the C/EBPα gene, that orchestrates C/EBPα transcription in vivo. Depletion of ADINR leads to a severe adipogenic def ...[more]

PMID: 26489893

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Project description:BackgroundMesenchymal stem cells (MSCs) are pluripotent stem cells that can differentiate via osteogenesis and adipogenesis. The mechanism underlying MSC lineage commitment still remains incompletely elucidated. Understanding the regulatory mechanism of MSC differentiation will help researchers induce MSCs toward specific lineages for clinical use. In this research, we intended to figure out the long noncoding RNA (lncRNA) that plays a central role in MSC fate determination and explore its application value in tissue engineering.MethodsThe expression pattern of lncRNAs during MSC osteogenesis/adipogenesis was detected by microarray and qRT-PCR. Lentivirus and siRNAs were constructed to regulate the expression of lncRNA repressor of adipogenesis (ROA). MSC osteogenesis/adipogenesis was evaluated by western blot and alizarin red/oil red staining. An adipokine array was used to select the paracrine/autocrine factor PTX3, followed by RNA interference or recombinant human protein stimulation to confirm its function. The activation of signaling pathways was also detected by western blot, and a small molecule inhibitor, SCH772984, was used to inhibit the activation of the ERK pathway. The interaction between ROA and hnRNP A1 was detected by RNA pull-down and RIP assays. Luciferase reporter and chromatin immunoprecipitation assays were used to confirm the binding of hnRNP A1 to the PTX3 promotor. Additionally, an in vivo adipogenesis experiment was conducted to evaluate the regulatory value of ROA in tissue engineering.ResultsIn this study, we demonstrated that MSC adipogenesis is regulated by lncRNA ROA both in vitro and in vivo. Mechanistically, ROA inhibits MSC adipogenesis by downregulating the expression of the key autocrine/paracrine factor PTX3 and the downstream ERK pathway. This downregulation was achieved through transcription inhibition by impeding hnRNP A1 from binding to the promoter of PTX3.ConclusionsROA negatively regulates MSC adipogenesis through the hnRNP A1-PTX3-ERK axis. ROA may be an effective target for modulating MSCs in tissue engineering.

Dataset Information

Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBPα.

Publications

Long Noncoding RNA ADINR Regulates Adipogenesis by Transcriptionally Activating C/EBPα.

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