Abstract
Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are involving in diverse cellular processes. However, their roles in reprogramming of gene expression profiles during lineage commitment and maturation of mesenchymal stem cells (MSCs) remain poorly understood. In the current study, we characterize the expression of a lncRNA, HoxA-AS3, during the differentiation of MSCs. We showed that HoxA-AS3 is increased upon adipogenic induction of MSCs, while HoxA-AS3 remains unaltered during osteogenic induction. Silencing of HoxA-AS3 in MSCs resulted in decreased adipogenesis and expression of adipogenic markers, PPARG, CEBPA, FABP4 and ADIPOQ. Conversely, knockdown of HoxA-AS3 expression in MSCs exhibited an enhanced osteogenesis and osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP1. Mechanistically, HoxA-AS3 interacts with Enhancer Of Zeste 2 (EZH2) and is required for H3 lysine-27 trimethylation (H3K27me3) of key osteogenic transcription factor Runx2. Our data reveal that HoxA-AS3 acts as an epigenetic switch that determines the lineage specification of MSC.
Highlights
Mesenchymal Stem Cells (MSCs) have multiple differentiation potential and low immunogenicity and serve as an excellent option for regenerative medicine, tissue engineering and clinical therapy
LncRNA HoxA-AS3 is required for adipogenesis of human MSCs (hMSCs)
Our results showed HoxA-AS3 expression was elevated 3 days onwards after adipogenic induction and reached the peak at 2 weeks (Figure 1A), suggesting that HoxA-AS3 might play a role in the adipogenesis of hMSCs
Summary
Mesenchymal Stem Cells (MSCs) have multiple differentiation potential and low immunogenicity and serve as an excellent option for regenerative medicine, tissue engineering and clinical therapy. The differentiation of MSC is regulated by specific growth factors, signaling molecules and epigenetic modifications [1, 2]. These regulatory factors together define a selective transcription of discrete combination of genes, which define a differentiation program and determine the specific lineage and phenotype. The expression lncRNAs is localized in the nucleus and is more tissue-specific compared with protein-coding transcripts [4]. LncRNAs can be associated with transcription factors to regulate gene activation or repression. LncRNAs can function as scaffold for transcription factors and guide the transcriptional activities across the genome in cis or trans [7]. 20% of mammalian lncRNAs, including HOTAIR, bind to the polycomb repressive complex (PRC2)
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