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      Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells

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          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.

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          Suppression of progenitor differentiation requires the long noncoding RNA ANCR.

          Markus Kretz, Dan Webster, Ross Flockhart … (2012)
          Long noncoding RNAs (lncRNAs) regulate diverse processes, yet a potential role for lncRNAs in maintaining the undifferentiated state in somatic tissue progenitor cells remains uncharacterized. We used transcriptome sequencing and tiling arrays to compare lncRNA expression in epidermal progenitor populations versus differentiating cells. We identified ANCR (anti-differentiation ncRNA) as an 855-base-pair lncRNA down-regulated during differentiation. Depleting ANCR in progenitor-containing populations, without any other stimuli, led to rapid differentiation gene induction. In epidermis, ANCR loss abolished the normal exclusion of differentiation from the progenitor-containing compartment. The ANCR lncRNA is thus required to enforce the undifferentiated cell state within epidermis.
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            Downregulated LncRNA-ANCR promotes osteoblast differentiation by targeting EZH2 and regulating Runx2 expression.

            Lin Zhu, Pei Xu (2013)
            Long noncoding RNAs (lncRNAs) are key regulators of diverse biological processes such as transcriptional regulation, cell growth and differentiation. Previous studies have demonstrated that the lncRNA-ANCR (anti-differentiation ncRNA) is required to maintain the undifferentiated cell state within the epidermis. However, little is known about whether ANCR regulates osteoblast differentiation. In this study, we found that the ANCR expression level is significantly decreased during hFOB1.19 cell differentiation. ANCR-siRNA blocks the expression of endogenous ANCR, resulting in osteoblast differentiation, whereas ANCR overexpression is sufficient to inhibit osteoblast differentiation. We further demonstrated that ANCR is associated with enhancer of zeste homolog 2 (EZH2) and that this association results in the inhibition of both Runx2 expression and subsequent osteoblast differentiation. These data suggest that ANCR is an essential mediator of osteoblast differentiation, thus offering a new target for the development of therapeutic agents to treat bone diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
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              H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA

              Wei-Cheng Liang, Wei-Ming Fu, Zhen-Yu Wang … (2016)
              Bone homeostasis is tightly orchestrated and maintained by the balance between osteoblasts and osteoclasts. Recent studies have greatly expanded our understanding of the molecular mechanisms of cellular differentiation. However, the functional roles of non-coding RNAs particularly lncRNAs in remodeling bone architecture remain elusive. In our study, lncRNA H19 was found to be upregulated during osteogenesis in hMSCs. Stable expression of H19 significantly accelerated in vivo and in vitro osteoblast differentiation. Meanwhile, by using bioinformatic investigations and RIP assays combined with luciferase reporter assays, we demonstrated that H19 functioned as an miRNA sponge for miR-141 and miR-22, both of which were negative regulators of osteogenesis and Wnt/β-catenin pathway. Further investigations revealed that H19 antagonized the functions of these two miRNAs and led to de-repression of their shared target gene β-catenin, which eventually activated Wnt/β-catenin pathway and hence potentiated osteogenesis. In addition, we also identified a novel regulatory feedback loop between H19 and its encoded miR-675-5p. And miR-675-5p was found to directly target H19 and counteracted osteoblast differentiation. To sum up, these observations indicate that the lncRNA H19 modulates Wnt/β-catenin pathway by acting as a competing endogenous RNA, which may shed light on the functional role of lncRNAs in coordinating osteogenesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 27 September 2016
                Publication date (Electronic): 23 August 2016
                Volume: 7
                Issue: 39
                Pages: 63561-63570
                Affiliations
                1 Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China
                2 School of Dentistry, University of California, Los Angeles, CA, USA
                3 Department of Physiology, Center for Diabetes, Obesity and Metabolism, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, Guangdong, China
                4 Henan Key Laboratory of Neural Regeneration and Repairment, The First affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China
                5 Department of Obstetrics and Gynecology, University of California, Irvine, CA, USA
                Author notes
                Correspondence to: Yi-Zhou Jiang, jiangyz@ 123456szu.edu.cn
                Article
                Publisher ID: 11538
                DOI: 10.18632/oncotarget.11538
                PMC ID: 5325385
                PubMed ID: 27566578
                SO-VID: eeb6323d-396e-4575-bb70-1fc40f7e1f71
                Copyright © Copyright: © 2016 Zhu et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 16 June 2016
                Date accepted : 15 August 2016
                Categories
                Subject: Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: mesenchymal stem cells,hoxa-as3,lineage specification,enhancer of zeste homolog 2,long non-coding rna
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: mesenchymal stem cells, hoxa-as3, lineage specification, enhancer of zeste homolog 2, long non-coding rna

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