Alternative role of noncoding RNAs: coding and noncoding properties

Alternative role of noncoding RNAs: coding and noncoding properties 非编码RNA的选择性作用:编码与非编码特性研究进展 1 first-author 2 3 4 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:liuzy271@163.com †E-mail:liuzy271@163.com liuzy271@163.com Department of Emergency Internal Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China Department of Emergency Internal Medicine, Shanghai East Hospital, Tongji University, Shanghai 200120, China Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China Department of Laboratory Diagnostics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China Department of Laboratory Diagnostics, Changhai Hospital, Second Military Medical University, Shanghai 200433, China Kunming General Hospital of Chengdu Military Command, Kunming 650032, China Kunming General Hospital of Chengdu Military Command, Kunming 650032, China Noncoding RNAs (ncRNAs) have played a critical role in cellular biological functions. Recently, some peptides or proteins originating from annotated ncRNAs were identified in organism development and various diseases. Here, we briefly review several novel peptides translated by annotated ncRNAs and related key functions. In addition, we summarize the potential mechanism of bifunctional ncRNAs and propose a specific “switch” triggering the transformation from the noncoding to the coding state under certain stimuli or cellular stress. The coding properties of ncRNAs and their peptide products may provide a novel horizon in proteomic research and can be regarded as a potential therapeutic target for the treatment of various diseases. 非编码RNA在细胞生物学功能中发挥着重要作用.近年来,研究人员在生物发育和多种疾病中发现了一些由非编码RNA(ncRNA)编码产生的多肽或蛋白质.在本文中,我们简要总结了几种由ncRNA翻译的微肽分子及其功能.此外,我们还总结了调控ncRNA的可能机制,并且提出了一个生物"开关",即细胞在一定的刺激或应激状态下,能够触发ncRNA分子由非编码状态到编码状态的转换.ncRNA的潜在编码特性及其微肽产物为蛋白质组学研究提供了一个新的视角,有希望为多种疾病提供新的治疗靶点. Non-coding RNA Biological function Micropeptides Cellular stress 非编码RNA 生物功能 微肽 细胞应激 Noncoding RNAs (ncRNAs) have played a critical role in cellular biological functions. Recently, some peptides or proteins originating from annotated ncRNAs were identified in organism development and various diseases. Here, we briefly review several novel peptides translated by annotated ncRNAs and related key functions. In addition, we summarize the potential mechanism of bifunctional ncRNAs and propose a specific “switch” triggering the transformation from the noncoding to the coding state under certain stimuli or cellular stress. The coding properties of ncRNAs and their peptide products may provide a novel horizon in proteomic research and can be regarded as a potential therapeutic target for the treatment of various diseases. In eukaryotic genomes, the majority of DNA sequences without coding capability were transcribed into a large number of ncRNAs. These include housekeeping RNAs, such as transfer RNAs (tRNAs), ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs), and non-housekeeping RNAs, such as microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) (Carninci et al., 2005 2005 ). In the human genome, Hon et al. ( 2017 2017 ) systematically assessed the diversity of lncRNAs using Functional Annotation of the Mammalian Genome 5 (FANTOM5) cap analysis and obtained a better understanding of the function of nearly 20 000 human lncRNAs through online databases. This can help researchers conduct functional studies of lncRNA candidates. Researchers believed that ncRNAs are “dark matters” and play an essential role in biological development and pathological processes, and many excellent reviews have summarized their cellular functions (Cech and Steitz, 2014 2014 ; Dey et al., 2014 2014 ; Xu et al., 2017 2017 ). Translation of messenger RNA (mRNA) is an essential process in biological regulation. Canonically, proteins were translated from eukaryotic mRNAs containing long open reading frame (ORF) by recognizing the m7GpppX cap structure at the 5' end of the transcript (Sonenberg and Hinnebusch, 2009 2009 ). In addition, a ribosome can also initiate the translation process in a cap-independent manner, termed the internal ribosome entry site (IRES). IRES is an RNA regulatory element and is critical for the production of many human and viral proteins (Lozano et al., 2015 2015 ). In many positive-strand RNA viruses or positive-sense single-stranded RNA ([+]ssRNA) viruses, the transcripts are naturally uncapped and rely heavily on the IRES-dependent manner for protein synthesis (den Boon et al., 2010 2010 ). Because of the little extensive ORF which is fewer than 100 codons, ncRNAs display limited translation property (Eddy, 1999 1999 ; Costa, 2005 2005 ). However, with the advances of large-scale genome analysis, some realized that the “noncoding” is an unreliable annotation of these small ORFs (Aspden et al., 2014 2014 ; Mumtaz and Couso, 2015 2015 ). A large portion of identified ncRNAs with small ORFs have the capacity of coding peptides and play specific roles in Escherichia coli (Hemm et al., 2008 2008 ), plants (Röhrig et al., 2002 2002 ; Hanada et al., 2013 2013 ; Okamoto et al., 2014 2014 ), Drosophila (Kondo et al., 2007 2007 , 2010 2010 ; Magny et al., 2013 2013 ), zebrafish (Pauli et al., 2014 2014 ), mice (Crappé et al., 2013 2013 ; Anderson et al., 2015 2015 ; Nelson et al., 2016 2016 ), and the human (Slavoff et al., 2013 2013 ; Anderson et al., 2015 2015 ; Nelson et al., 2016 2016 ). These studies indicated that many ncRNAs have coding features (Chew et al., 2013 2013 ). Recent advances in research on ribosome function revealed that translation can initiate at codons other than AUG (Kearse and Wilusz, 2017 2017 ). For example, death-associated protein 5 (DAP5) is a member of the eukaryotic translation initiation factor 4G (eIF4G) family of translation initiation factors and plays an important role in IRES-mediated translation, which is only encoded from the initiation codon GUG in various species (Chang and Wang, 2004 2004 ; Takahashi et al., 2005 2005 ; Liberman et al., 2015 2015 ). Some repeat sequences within RNA regions are typically considered noncoding. These can also initiate non-AUG translation and produce toxic proteins which are associated with neurodegenerative diseases. CAG and CUG repeat RNA translation is associated with spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1) (Zu et al., 2011 2011 ). GGGGCC/CCCCGG repeats in C9orf72 (C9ALS/FTD) gene occur in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (Ash et al., 2013 2013 ; Mori et al., 2013 2013 ). Previous studies suggested that these small ORFs in ncRNAs may translate in a conventional way from an AUG codon to a stop codon (Stammers et al., 2015 2015 ; Magny et al., 2013 2013 ). The non-AUG translation initiation of ncRNAs is rarely reported and calls for further research. In cellular development, ncRNAs play critical roles in biological regulation such as cell proliferation, organ development, and immune response (Xie and Liu, 2015 2015 ; Gore-Panter et al., 2016 2016 ; Li et al., 2016 2016 ; Liu and Liu, 2016 2016 ). Some ncRNAs contain coding and noncoding properties and act as bifunctional regulators. The specific biological features of ncRNAs with coding potential are largely unknown. The transformation mechanisms between noncoding and coding conditions of a transcript are unclear. Here, we briefly review several novel peptides translated by ncRNAs and summarize the possible mechanisms of the transformation between the coding and the noncoding states. Researchers conventionally believed that transcriptions with small ORFs are hardly translated and the polypeptides are unstable in cytoplasm, so these transcriptions are classified as ncRNAs (Basrai et al., 1997 1997 ). Recently, the annotation of “noncoding” looks unreliable and the function of the small ORF is hindered by their sequence length (Aspden et al., 2014 2014 ). The new experimental technique of ribosome profiling has found that there are a large number of ribosome-protected fragments (RPFs) associated with many previously annotated ncRNAs (Mumtaz and Couso, 2015 2015 ; Calviello et al., 2016 2016 ). These ncRNAs share similar characters with 5' leaders of coding mRNAs (Vandin et al., 2012 2012 ) and contain small ORFs (Chu et al., 2015 2015 ; Calviello et al., 2016 2016 ). Both observations suggest the encoding potential of ncRNAs. Several research groups have identified some new peptides or proteins translated by specific ncRNAs and function in various organisms (Hemm et al., 2008 2008 ; Pauli et al., 2014 2014 ; Anderson et al., 2015 2015 ; Nelson et al., 2016 2016 ; Pueyo et al., 2016 2016 ). Here, we have reviewed several novel identified products translated by ncRNAs and summarized them briefly in Table 1 1 . MLN: myoregulin; SCL: sarcolamban; DWORF: dwarf open reading frame; SPAR: small regulatory polypeptide of amino acid response; HOXB-AS3: HOXB cluster antisense RNA 3; STORM: stress-and tumor necrosis factor-α (TNF-α)-activated open reading frame (ORF) micropeptide; SERCA: sarcoplasmic reticulum Ca 2+ -ATPase; mTORC1: mechanistic target of rapamycin complex 1; SRP19: signal recognition particle 19 Peptide Size (kDa) Species Function Reference  MLN ~5 Mouse Suppressing SERCA activity in skeletal muscle Anderson et al., 2015 2015  SCL ~3 Drosophila Suppressing SERCA activity in cardiac muscle Magny et al., 2013 2013  DWORF ~4 Mouse Enhancing SERCA activity in skeletal muscle Nelson et al., 2016 2016  SPAR ~10 Mouse Suppressing mTORC1 activation in skeletal muscle Matsumoto et al., 2017 2017  Myomixer ~9 Mouse Promoting myoblast fusion during muscle development Bi et al., 2017 2017  HOXB-AS3 ~6 Human Suppressing colon cancer growth Huang et al., 2017 2017  STORM ~6 Human Reducing the interaction of SRP19 and 7SL RNA Min et al., 2017 2017  Circ-ZNF609 encoded 30–40 Mouse, human Unknown Legnini et al., 2017 2017  CircMbl3 encoded 37.04 Drosophila Unknown Pamudurti et al., 2017 2017 In normal muscle tissue, sarcoplasmic reticulum Ca 2+ -ATPase (SERCA) regulates Ca 2+ uptake into the sarcoplasmic reticulum (SR) and takes responsibility for subsequent contraction-relaxation cycles in cardiac and skeletal muscle. Phospholamban (PLN) and sarcolipin (SLN) regulate SERCA activity and modulate Ca 2+ levels in SR (Stammers et al., 2015 2015 ). Anderson et al. ( 2015 2015 ) discovered a new micropeptide, named myoregulin (MLN), that directly interacts with SERCA and restrains Ca 2+ into SR. MLN is coded by a specific RNA which previously was annotated as a putative lncRNA in skeletal muscle and robustly expressed in all adult skeletal muscle. Researchers observed that SR Ca 2+ levels are obviously enhanced in MLN knockout mice, suggesting that MLN behaves similar fashion to SLN and PLN (Anderson et al., 2015 2015 ). Calcium ATPase at 60A (Ca-P60A) is the invertebrate homolog of SERCA in Drosophila cardiac muscle and is modulated by micropeptide sarcolamban (SCL) which is encoded by a functional small ORF of almost 30 amino acids (aa) in a putative ncRNA (Magny et al., 2013 2013 ). In addition, SCL, SLN, and PLN are putative homologs in both structure and function, regulating Ca 2+ uptake at the SR by interacting with SERCA or Ca-P60A. Nelson et al. ( 2016 2016 ) recently identified a peptide, named dwarf open reading frame (DWORF), which acts in an opposite way to SERCA inhibitors. DWORF promotes SR Ca 2+ uptake by enhancing SERCA activity. In DWORF overexpression mice, peak Ca 2+ transient amplitude and SR Ca 2+ load are significantly increased while decreasing Ca 2+ decay time in cardiomyocytes during each contraction-relaxation cycle of cardiac muscle. Recently, the discovery of a small regulatory polypeptide of amino acid response (SPAR), which is encoded by the lncRNA LINC00961, showed another surprising function of polypeptide in muscle tissue. SPAR specifically suppresses mechanistic target of rapamycin complex 1 (mTORC1) activation by interacting with the lysosomal vacuolar H + -ATPase (V-ATPase). Down-regulating SPAR expression, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 engineering, increases mTORC1 activity and promotes muscle regeneration in the mice model (Matsumoto et al., 2017 2017 ). In addition, a muscle-specific peptide, called Myomixer, is translated by lncRNA (LOC101929726) and plays an essential role for skeletal muscle formation during development. Myomixer expresses in the plasma membrane where it promotes fibroblast-fibroblast fusion and fibroblast-myoblast fusion by interacting with Myomaker, a fusogenic membrane protein (Bi et al., 2017 2017 ). In colon cancer, a conserved 53-aa peptide was translated by lncRNA HOXB cluster antisense RNA 3 (HOXB-AS3) (Huang et al., 2017 2017 ). Compared with normal patients, HOXB-AS3 peptide was down-regulated in colon cancer patients and indicated poor prognoses. Research further revealed that low expression of HOXB-AS3 peptide impacts colon cancer cell metabolism by regulating pyruvate kinase M (PKM) alternative splicing pattern (Huang et al., 2017 2017 ). Eukaryotic translation initiation factor 4E (eIF4E) is one of one of the translation initiation factors and can be phosphorylated by mammalian Ste20-like kinase 1 (MST1). Phosphorylated eIF4E weakly interacts with 5' cap to inhibit translation of target mRNAs such as eukaryotic translation initiation factor 2 α (eIF2-α), eukaryotic translation elongation factor 2 (eEF2), and chaperonin containing t -complex polypeptide 1 (TCP1) subunit 2 (CCT2) mRNAs, but activates translation of linc00689 to produce a micropeptide named stress-and tumor necrosis factor-α (TNF-α)-activated ORF micropeptide (STORM). STORM shows high similarity with signal recognition particle 19 (SRP19) and acts as a competing peptide to inhibit SRP19 interaction with 7SL RNA (Min et al., 2017 2017 ). It was recently found that circRNAs are able to encode peptide in a cap-independent way with an IRES. Circular (circ)-ZNF609 is a circRNA and plays a crucial role during myogenesis (Legnini et al., 2017 2017 ). Bioinformatic analysis of the circ-ZNF609 sequence showed the existence of an ORF and two proteins originating from the translation of circ-ZNF609. Heat shock significantly increased the translation activation of circ-ZNF609 (Legnini et al., 2017 2017 ). In Drosophila , Pamudurti et al. ( 2017 2017 ) uncovered that circRNA Mbl1 is generated from the muscleblind locus and can encode a protein in cap-independent way. Meanwhile, the translation efficiency of circRNA Mbl1 is affected by starvation and a transcription factor, forkhead box O (FOXO) (Pamudurti et al., 2017 2017 ). These findings indicated a possible coding mechanism of ncRNAs responding to cellular stress or stimulation. Bifunctional ncRNAs containing coding and noncoding properties exist in diverse genomes and transcriptomes. Newly developed gene scanning techniques, such as ribosome profiling and RNA binding protein immunoprecipitation (RIP)-sequence, have revealed the abundant existence of ncRNAs containing small ORF and associated with ribosome possessing coding. These had been neglected previously. However, when does this form of translation driven by ncRNAs occur? Are there any existing associations between encoded peptides or proteins and cellular circumstances? If the peptides or proteins were translated after specific cellular stress or stimulation, how are these cases regulated? Are these encoded peptides or proteins driven from canonical cap-dependent or cap-independent translation? All these remain largely unanswered questions and require further exploration. Here, we propose a hypothesis that, in biological and pathological processes, there might exist a transformation mechanism between the coding and noncoding properties of ncRNAs. Generally, ncRNAs regulate the expression of other genes in post-transcriptional modification. In certain circumstances, it may trigger this “switch” by modifying ncRNAs sequences to activate the translation activity of ncRNAs (Fig. 1 1 ). In nucleus, ncRNA was transcribed from primary RNA (pri-RNA). The major function of microRNAs (miRNAs) was assembled into RNA-inducing silencing complex (RISC) to regulate the expression of target messenger RNA (mRNA). For long noncoding RNAs (lncRNAs), some of them can target proteins and display different functions in cellular development. Other lncRNAs with small open reading frame (ORF) may combine with the ribosome showing coding potential. It has been reported that internal ribosome entry site (IRES) and N 6 -methyladenosine (m 6 A) motif were essential for certain circular RNA (circRNA) translation. In some specific circumstances or stimuli, such as tumorigenesis, heat shock, and starvation, certain ncRNAs with coding potential may interact with the ribosome and encode polypeptides in the cytoplasm IRESs are located within the 5'-untranslated regions (UTRs) mostly and have complex structures, such as stem loops and pseudoknots, mediating translation when cap-dependent translation is compromised under some conditions (Komar and Hatzoglou, 2011 2011 ). CircRNA with IRES can be spliced functionally and translated into protein (Wang and Wang, 2015 2015 ). Yang et al. ( 2017 2017 ) found the protein translation of circRNA can be initiated though N 6 -methyladenosine (m 6 A) motif and catalyzed by m 6 A writers, methyltransferase-like 3 (METTL3) and METTL14. This indicated the general effect of m 6 A on circRNA translation. In addition to specific ncRNA structure, sequence modification, the phosphorylation of eIF4E (Min et al., 2017 2017 ) and certain stimuli can promote the favored translation of ncRNAs, such as neoplastic environment (Huang et al., 2017 2017 ), hot shock (Legnini et al., 2017 2017 ), and starvation (Pamudurti et al., 2017 2017 ), as summarized above. More interestingly, the transformation from protein-coding mRNA to ncRNA also exists. Williamson et al. ( 2017 2017 ) recently found that ultraviolet (UV) irradiation induces a switch from a long protein-coding activating signal cointegrator 1 complex subunit 3 (ASCC3) mRNA to a short alternative last exon (ALE) transcript isoform which functions as lncRNA. The UV-induced ASCC3 short isoform regulates transcription recovery and plays an antagonistic role compared with long ASCC3 isoform. The coding pattern transition of mRNA can be regulated by alternative splicing. Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) acts as a splicing factor and directly binds to exon 12 of phosphatase 1 nuclear targeting subunit ( PNUTS ) pre-mRNA, and then generates a noncoding transcription of PNUTS (Grelet et al., 2017 2017 ). In breast cancer, the expression of lncRNA- PNUTS is increased and regulates epithelial-mesenchymal transition (EMT) by binding miR-205 competitively (Grelet et al., 2017 2017 ). Genome screening and sequence technique have uncovered a large number of diverse transcriptions arranging from animalcules to mammals. Coding and noncoding RNAs (cncRNAs) are a specific group of RNAs, possessing both the coding and noncoding properties, and this is considered as bifunctional RNAs in transcriptomes. The functions and sources of cncRNAs in cellular development have been reviewed previously (Nam et al., 2016 2016 ; Sampath and Ephrussi, 2016 2016 ). These findings and facts strongly indicate that there is a “coordinator” regulating the transformation between alternative roles of ncRNAs. Tumorigenesis is a complicated process involving many steps. In this process, tumor cells are often subjected to a severe microenvironment such as hypoxia, nutrient deprivation, and other stress induced by rapid cell division and defective tumor vasculature (Leprivier et al., 2015 2015 ). To manage these stresses, the canonical cap-dependent mRNA translation is depressed in order to keep an energetic balance but some proteins, such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), translated though cap-independent means, are increased (Leprivier et al., 2015 2015 ). The study of ncRNAs encoding activity in tumorigenesis may initiate a promising field and benefit clinical tumor diagnosis and therapy. In summary, transcriptomes and genomes are far more complicated than previously thought. 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