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Long Non-Coding RNA MEG3 in Cellular Stemness

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Long Non-Coding RNA MEG3 in Cellular Stemness International Journal of Molecular Sciences Review Long Non-Coding RNA MEG3 in Cellular Stemness Pei-Fang Hsieh 1,2,†, Cheng-Chia Yu 3,4,5,†, Pei-Ming Chu 6 and Pei-Ling Hsieh 6,* 1 Department of Urology, E-Da Hospital, Kaohsiung 82445, Taiwan; [email protected] 2 Department of Medical Laboratory Science and Biotechnology, Chung-Hwa University of Medical Technology, Tainan 71703, Taiwan 3 Institute of Oral Sciences, Chung Shan Medical University, Taichung 40201, Taiwan; [email protected] 4 Department of Dentistry, Chung Shan Medical University Hospital, Taichung 40201, Taiwan 5 School of Dentistry, Chung Shan Medical University, Taichung 40201, Taiwan 6 Department of Anatomy, School of Medicine, China Medical University, Taichung 404333, Taiwan; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Long non-coding RNAs (lncRNAs) regulate a diverse array of cellular processes at the transcriptional, post-transcriptional, translational, and post-translational levels. Accumulating evidence suggests that lncRNA MEG3 exerts a large repertoire of regulatory functions in cellular stemness. This review focuses on the molecular mechanisms by which lncRNA MEG3 functions as a signal, scaffold, guide, and decoy for multi-lineage differentiation and even cancer progression. The role of MEG3 in various types of stem cells and cancer stem cells is discussed. Here, we provide an overview of the functional versatility of lncRNA MEG3 in modulating pluripotency, differentiation, and cancer stemness. Keywords: long non-coding RNA MEG3; embryonic stem cells; mesenchymal stem cells; cancer stem cells Citation: Hsieh, P.-F.; Yu, C.-C.; Chu, P.-M.; Hsieh, P.-L. Long Non-Coding RNA MEG3 in Cellular Stemness. Int. 1. Introduction J. Mol. Sci. 2021, 22, 5348. https:// doi.org/10.3390/ijms22105348 Maternally expressed gene 3 (MEG3), also known as gene trap locus 2 (Gtl2), was identified by gene trap insertion, and tightly linked to paternally expressed Delta-like 1 Academic Editor: Manching Ku (Dlk1) gene at chromosome 14q32.3 within Dlk1-Dio3 locus [1–3]. The Dlk1 gene encodes a transmembrane protein that contains multiple epidermal growth factor repeats and Received: 27 April 2021 belongs to the Notch signaling family [4]. On the other hand, MEG3 is widely expressed Accepted: 17 May 2021 during development in the paraxial mesoderm, the developing central nervous system, Published: 19 May 2021 and the epithelia of the salivary glands, kidney, and pancreas [1]. Due to the lack of known functional proteins encoded by the small open reading frames of this gene transcript, MEG3 Publisher’s Note: MDPI stays neutral has been considered as a long non-coding RNA (lncRNA) for tumor suppression [5]. with regard to jurisdictional claims in Conventionally, non-coding RNAs can be divided into lncRNAs that have more published maps and institutional affil- than 200 nucleotides in length and the remaining RNAs are recognized as “small” non- iations. coding RNAs, such as microRNAs (miRNAs; ~22 nucleotides), piwiRNAs (piRNAs; ~26–31 nucleotides), or small nucleolar RNAs (snoRNAs; ~60–300 nucleotides). MiRNAs have been known to repress the expression of a target gene with partially complementary binding sites in its 30 untranslated region (30UTR) [6]. As for lncRNAs, diverse func- Copyright: © 2021 by the authors. tions have been discovered to regulate various biological processes, including serving as Licensee MDPI, Basel, Switzerland. scaffolds, molecular signals, guides, or decoys (see review [7]; Figure1). Briefly, some This article is an open access article lncRNAs occur at a certain time and space to integrate diverse stimuli (signal), or they distributed under the terms and may initiate cis- or trans-regulation of gene expression (guide). Additionally, they can conditions of the Creative Commons function as platforms to assemble relevant molecular components to promote or repress Attribution (CC BY) license (https:// gene expression (scaffold). Moreover, lncRNAs may bind to their targets or miRNAs creativecommons.org/licenses/by/ (decoy) to inhibit their action. A similar concept proposes that lncRNAs may be one kind 4.0/). Int. J. Mol. Sci. 2021, 22, 5348. https://doi.org/10.3390/ijms22105348 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 11 Int. J. Mol. Sci. 2021, 22, 5348 2 of 11 action. A similar concept proposes that lncRNAs may be one kind of competing endoge- nousof competing RNA (ceRNAs) endogenous and serve RNA as (ceRNAs) miRNA sponges and serve to asmodulate miRNA the sponges distribution to modulate of the miRNAsdistribution on oftheir miRNAs targets on via their miRNA targets response via miRNA elements response [8]. elements The interplay [8]. The interplaybetween lncRNAsbetween lncRNAsand miRNAs and miRNAshas been has extensively been extensively studied studied and many and manyreports reports indicate indicate that lncRNAsthat lncRNAs may modulate may modulate the expression the expression of certain of certainmRNAs mRNAs by acting by as acting molecular as molecular decoys anddecoys sequestering and sequestering miRNAs miRNAs to affect tovarious affect variousdisease states. disease states. FigureFigure 1. 1. GeneralGeneral modes modes of of action action of of lncRNAs. lncRNAs. (Adapted (Adapted from from [7]) [7]). AA number number of of studies studies have have suggested suggested that that the the expression expression of of MEG3 MEG3 is is downregulated downregulated inin several several types types of of cancer cancer cells cells [5,9,10], [5,9,10 ],and and DNA DNA methylation methylation has has been been proven proven to toplay play a significanta significant role role in silencing in silencing MEG3 MEG3 in tumors in tumors [11]. [ 11Aside]. Aside fromfrom functioning functioning as a tumor as a tumor sup- pressor,suppressor, emerging emerging evidence evidence suggests suggests that that ME MEG3G3 may may be beinvolved involved in in the the regulation regulation of of stemness.stemness. In In this this review, review, we brieflybriefly summarizedsummarized recent recent studies studies about about the the effect effect of of MEG3 MEG3 on onthe the differentiation differentiation of of embryonic embryonic and and mesenchymal mesenchymal stem stem cells cells as wellas well as theas the aggressiveness aggressive- nessof cancer of cancer stem stem cells. cells. We focusedWe focused on targets/interacting on targets/interacting factors factors and and molecular molecular mechanisms mecha- nismsto provide to provide an insight an insight into the into multiple the multiple functions functions of MEG3 of MEG3 in cellular in cellular stemness. stemness. 2.2. Stem Stem Cells Cells 2.1. Embryonic Stem Cells 2.1. Embryonic Stem Cells During embryonic development and adulthood, MEG3 has been detected in the During embryonic development and adulthood, MEG3 has been detected in the mouse forebrain [12] and corticospinal neurons [13], indicating MEG3 may play a part in mouse forebrain [12] and corticospinal neurons [13], indicating MEG3 may play a part in the maturation of the central nervous system. Besides, MEG3 has been found to be highly the maturation of the central nervous system. Besides, MEG3 has been found to be highly expressed in human embryonic stem cells (hESCs) and to affect their neural differentiation expressedcapacities in [14 human,15]. Embryoid embryonic bodies stem cells derived (hESCs from) and hESCs to affect with their undetectable neural differentiation MEG3 have capacitiesbeen found [14,15]. to exhibit Embryoid unusual bodies morphologies derived alongfrom hESCs with decreased with undetectable expression MEG3 of the neuralhave beenstem found cell marker, to exhibit paired unusual box 6morphologies (PAX6) [14]. Knockdownalong with decreased of MEG3 inexpression hESCs results of the inneu- the raldownregulation stem cell marker, of various paired neuralbox 6 (PAX6) lineage genes.[14]. Knockdown Additionally, of theMEG3 neural in hESCs lineage-like results cells in thederived downregulation from hESCs of with various undetectable neural lineage MEG3 displaygenes. Addition a lower expressionally, the neural of lineage-specific lineage-like cellsmarkers derived and from form hESCs fewer with neurites undetectable [14], suggesting MEG3 thedisplay significance a lower expression of MEG3 in of the lineage- neural specificlineage markers differentiation and form of hESCs.fewer neurites [14], suggesting the significance of MEG3 in the neuralAdditionally, lineage differe MEG3ntiation has of been hESCs. found to interact with polycomb repressive complex-2 (PRC2)Additionally, via jumonji, MEG3 AT rich has interactivebeen found domain to interact 2 (JARID2), with polycomb and facilitate repressive the recruitment complex-2 (PRC2)of PRC2 via on jumonji, chromatin AT rich [15, 16interactive]. The potential domain site 2 (JARID2), where MEG3 and facilitate interacts the with recruitment PRC2 has also been described [17]. JARID2 is a crucial modulator of PRC2 enzymatic activity and is Int. J. Mol. Sci. 2021, 22, 5348 3 of 11 required for the multi-lineage differentiation of ESCs [18]. On the other hand, PRC2 is a histone methyltransferase for epigenetic silencing that works by providing the H3K27me3 repressive epigenetic mark [19]. A large number of lncRNAs have been thought to facilitate the recruitment of PRC2 to the correct chromatin sites [20], and MEG3 is one of them. It serves as a scaffold and bridges the PRC2/JARID2 complex to
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