3’UTR Diversity: Expanding Repertoire of RNA Alterations in Human mRNAs
Abstract
Genomic information stored in the DNA is transcribed to the mRNA and translated to proteins. The 3′ untranslated regions (3′UTRs) of the mRNA serve pivotal roles in post-transcriptional gene expression, regulating mRNA stability, translation, and localization. Similar to DNA mutations producing aberrant proteins, RNA alterations expand the transcriptome landscape and change the cellular proteome. Recent global analyses reveal that many genes express various forms of altered RNAs, including 3′UTR length variants. Alternative polyadenylation and alternative splicing are involved in diversifying 3′UTRs, which could act as a hidden layer of eukaryotic gene expression control. In this review, we summarize the functions and regulations of 3′UTRs and elaborate on the generation and functional consequences of 3′UTR diversity. Given that dynamic 3′UTR length control contributes to phenotypic complexity, dysregulated 3′UTR diversity might be relevant to disease development, including cancers. Thus, 3′UTR diversity in cancer could open exciting new research areas and provide avenues for novel cancer theragnostics.
INTRODUCTION
Evolutional features of human mRNA 3′UTRs
In general, the noncoding part of the genome has increased in size and complexity during evolution (Pesole et al., 2002). The average length of 5′UTRs is similar in metazoans; whereas, the 3′UTR is significantly longer in humans compared to other species (Mayr, 2016; Pesole et al., 2002; Sood et al., 2006; Wang et al., 2019) (Fig. 1). 3′-end sequencing also revealed that at least half of human genes could generate alternative 3′UTR isoforms from the same genes, demonstrating high diversity in 3′UTR in the human transcriptome (Derti et al., 2012; Hoque et al., 2013).
3′UTRs contain cis-regulatory elements recognized by trans-acting factors. Thus, changes in 3′UTR length could alter a number of regulatory elements (Ji et al 2009). In fact, many genes have alternative 3′UTR or contain internal introns which can switch 3′UTR length. Therefore, 3′UTR length changes could affect gene expression by fine-tuning and reprogramming the mRNA regulatory landscape in human cells (Navarro et al., 2021).
FUNCTIONS OF 3′UTRs
Stability control
Most mRNAs undergo stability regulation through specific sequences and structures in 3′UTRs, such as AU-rich elements (AREs), GU-rich elements, CA-rich elements, and miRNA-binding sequences. Some proteins bind to AREs and recruit the degradation machinery to ARE-containing mRNAs. For example, tristetraprolin (TTP) binds AREs within the 3′UTRs of mRNAs, such as tumor necrosis factor (TNF), prostaglandin-endoperoxide synthase 2 (PTGS2/cyclooxygenase-2, [COX-2]), vascular endothelial growth factor A (VEGFA), interleukin 10 (IL10), and immediate early response 3 (IER3), and promote mRNA degradation (Essafi-Benkhadir et al., 2007; Lai et al., 1999; 2006; Sawaoka et al., 2003).
In contrast, Hu-antigen R (HuR) protein binds AREs and stabilizes numerous mRNAs, increasing the corresponding protein level (Brennan and Steitz, 2001). HuR stabilizes mRNAs promoting tumor growth and cell survival, such as VEGFA, COX-2, TNF, CTNNB1//β-catenin, and interferon regulatory factor (IRF9) (Dean et al., 2001; Rothamel et al., 2021; Sengupta et al., 2003; Steinman, 2007; Thiele et al., 2006). It also stabilizes mRNAs involved in cell cycle regulation, such as cyclin dependent kinase inhibitor 1A (CDKN1A/p21) and cyclin (A2, B1, D1, and E1) (Giles et al., 2003; Guo and Hartley, 2006; Wang et al., 2000). In addition, mRNAs encoding prosurvival proteins such as FOS (c-fos) and B-cell CLL/lymphoma 2 (Bcl-2) are stabilized by HuR (Ishimaru et al., 2009; Wang et al., 2001). These data suggest that cis-regulatory elements in 3′UTR participate in the context- and condition-dependent mRNA stability control by binding to the combination of different sets of RBPs.
Translation control
3′UTRs also contain cis-regulatory elements related to translation control. During the development of Drosophila embryo, Hunchback mRNA 3′UTR forms an RNP complex with Pumilio, Nanos, and Brat protein, leading to translation repression for proper development in the posterior region of the embryo (Kuersten and Goodwin, 2003). Likewise, many developmental genes are expressed by the translation regulation mediated by 3′UTR-RNP complexes.
Different lengths of 3′UTR contribute to the translation efficiency control due to the presence or the absense of cis-regulatory elements. In the case of Uncoupling protein 1 (UCP1), the long 3′UTR isoform is predominant and contains the binding sites for the translation regulator, cytoplasmic polyadenylation element-binding protein 2 (CPEB2) (Chen et al., 2018). CPEB2 is required for associating the long 3′UTR isoform for the low-level translation of UCP1 mRNA in steady-state conditions, and translation upregulation in response to cold exposure or adrenaline (Chen et al., 2018). These data suggest the role of 3′UTRs for translation regulation by binding to many RBPs forming RNP complexes. 3′UTR-RNP–mediated translational regulation is also linked to mRNA localization, as described below.
Localization control
The subcellular localization of mRNA is investigated mostly in neurons (Andreassi and Riccio, 2009). Localized mRNA is translated in specific subcellular locations and allows the precise production of proteins in spatiotemporal patterns in response to neural activity. For example, calcium/calmodulin-dependent protein kinase II alpha (CaMK2A) regulates calcium signaling in the nervous system as a critical player in activity-dependent behavioral plasticity (Bae and Miura, 2020). In Drosophila, the 3′UTR of CaMK2A mRNA contains regulatory information necessary for local translation in presynaptic terminals (Broix et al., 2021). In mammals, the resting concentration of CaMK2A should be maintained extremely high, reaching up to 2% of the total protein in the hippocampus. This enrichment is achieved through the enhanced axoplasmic translation of CaMK2A mRNA, which is mediated by the RBP Mub and a 23-base Mub-recognition element in 3′UTR (Chen et al., 2022).
Actin beta (ACTB/β-actin) mRNA is another example of 3′UTR-mediated mRNA transport. 3′UTR of ACTB mRNA associated with the zipcode-binding protein 1 (ZBP1), also known as insulin-like growth factor 2 mRNA-binding protein (IGF2BP) (Wu et al., 2020). This association facilitates the transport of ACTB mRNAs to the specific locations in neurons, such as dendrites, in response to brain-derived neurotrophic factor (BDNF) (Wu et al., 2020). Overall, the 3′UTR of the ACTB mRNA is crucially involved in its transport and localization in neurons, which is essential for the proper development and function of the nervous system.
The control of mRNA localization is also investigated in Drosophila embryo. In the case of oskar mRNA, the 67-nt stem-loop structure in 3′UTRs is essential for transporting the mRNA from the nurse cells into the oocyte. This transport depends on the action of dynein and kinesin motor proteins, which use the oocyte entry signal to guide the mRNA to its proper location within the embryo (Bose et al., 2022; Jambor et al., 2014). Therefore, 3′UTRs of an mRNA molecule are critically involved in determining its subcellular localization and manipulating its translation. In this way, 3′UTRs can regulate the spatiotemporal expression of a gene and control when and where a protein is produced.
Multi-step control
During the lifecycle of mRNAs, some RBPs bind to 3′UTRs and affect multiple steps of post-transcriptional regulation (Moore, 2005). Such multifunctional RBPs associate with 3′UTRs of many mRNAs involved in critical downstream events. Quaking (QK) is an RBP with a STAR domain involved in compact myelin formation (Vernet and Artzt, 1997). QK binds to a specific sequence in the 3′UTRs of several mRNAs that encode proteins related to myelin formation. The QK response element (QRE) is “ACUAAY” in 3′UTRs of mRNAs, such as microtubule associated protein 1B (MAP1B), cyclin dependent kinase inhibitor 1B (CDKN1B/p27kip), and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) mRNAs (Larocque et al., 2005; Li et al., 2000; Zearfoss et al., 2011; Zhao et al., 2006).
Some proteins are newly found RBPs implicated in multiple 3′UTR-mediated control steps. For example, β-catenin is a Wnt-activated transcription factor and an adhesion protein. In addition, it also associates with ARE in 3′UTRs of COX-2 mRNAs as an RBP in colon cancer cells. COX-2 protein expression is regulated by mRNA stability and translation control by 3′UTR-binding β-catenin in the cytoplasm (Lee and Jeong, 2006). Furthermore, the interaction between β-catenin and COX-2 mRNA assembles a tertiary complex with the HuR protein, vital for the upregulation of COX-2 protein levels and colon cancer progression (Kim et al., 2012). Considering that COX-2 protein is the enzyme critical for synthesizing prostaglandins, a high level of β-catenin RBP might have significant pathological effects on cancer cells.
Another example is serine/arginine-rich splicing factor 3 (SRSF3). SRSF3 is a member of the serin/arginine-rich (SR) family proteins, acting in AS mainly in the nucleus. In addition, the shuttling activity of SRSF3 is linked to AS regulation, export, and translation in the cytoplasm (Park and Jeong, 2016). SRSF3 interacts with the 3′UTR of p21cip1/waf1 (CDKN1A) mRNA and represses translation in the cytoplasm (Kim et al., 2022).
These multifunctional RBPs are located in both the nucleus and cytoplasm and form 3′UTR-mediated RNP to control the multiple steps of mRNA metabolism. Further research is needed to fully understand the multiple roles of RBPs in 3′UTR-mediated mRNA regulation.
REGULATION OF 3′UTR FUNCTIONS
By the interplay of miRNA and RBPs
3′UTR functions are regulated by the crosstalk of miRNAs and RBPs, and cis-regulatory elements within 3′UTRs. miRNAs are small noncoding RNA molecules that are crucially involved in regulating gene expression by binding to complementary sequences in the 3′UTRs of the target mRNA. This binding can lead to the destabilization of mRNAs or the inhibition of their translation (Baek et al., 2008; Friedman et al., 2009). For example, VEGFA mRNA 3′UTR contains several regulatory elements, including CA-rich elements and miRNA-binding sequences. In normal conditions, miR-297 and miR-299 bind to the 3′UTR of the VEGFA mRNA leading to reduced expression of VEGFA proteins (Matoulkova et al., 2012). However, under hypoxic conditions, the silencing activity of miR-297 and miR-299 on VEGFA mRNA is inhibited by the binding of hnRNPL to CA-rich elements in 3′UTRs, allowing mRNAs to be continuously translated into proteins (Jafarifar et al., 2011). These data suggest that the interplay of miRNAs and RBPs are important for the condition-dependent regulation of 3′UTR activities.
The control of 3′UTR length also could affect miRNA-binding sites and leads to functional consequences (Nam et al., 2014). Thus, the dynamic regulation of 3′UTR length could play a significant role in development because it contributes to the gene expression patterns observed in different cell types and tissues. Likely, distinct sets of genes are differentially regulated by the interplay of miRNA and RBPs in a context- and condition-dependent manner (Hoffman et al., 2016).
By forming RNA granules
RNA granules in the cytoplasm are emerging as essential players in mRNA localization and translation regulation (Moore, 2005; Tian et al., 2020). RNA granules are specialized structures in assembled RNAs with RNP particles. Several RNA granules include transport RNPs, stress granules, and processing bodies (P-bodies) (Kiebler and Bassell, 2006). This compartmentalization creates cellular asymmetries, may enhance biological reactions, and promote molecular interactions required for cell growth and development (Tian et al., 2020). How RNAs assemble RNA granules? 3′UTRs within mRNAs could be key components in forming RNA granules. For example, the cytoplasmic polyadenylation element (CPE) in 3′UTR and its binding protein CPEB facilitate mRNA transport to dendrites in rat hippocampal neurons (Huang et al., 2003). 3′UTR-RNP granules are formed on CaMK2A, MAP2, and β-catenin mRNAs with CPEB, maskin, and eIF4E, for transporting corresponding mRNAs (Huang et al., 2003; Kundel et al., 2009; Rook et al., 2000).
Technical advances enhance cellular RNA granule visualization. In situ hybridization (ISH) demonstrated the bicoid and oskar RNP granules with Staufen double-strand binding protein in Drosophila oocytes (Huang et al., 2003; Kiebler and Bassell, 2006; St Johnston, 2005). Moreover, the improvement of in situ RNA visualization methods, such as single-molecular fluorescent ISH (smFISH) and RNAscope® made it possible to observe oskar RNP granules with scaffold protein Bruno and Hrp48 (Bae and Miura, 2020; Bose et al., 2022; de Planell-Saguer et al., 2010). Further enhancement of mRNA visualization techniques will be required to elucidate and visualize the 3′UTR-dependent RNA granule localization.
GENERATING 3′UTR LENGTH DIVERSITY
APA in 3′UTR
Cleavage and polyadenylation is a critical step in the maturation of 3′UTR ends of most eukaryotic mRNAs (Mitschka and Mayr, 2022). The polyadenylation process begins the recognition of specific sequences in the mRNA molecule by the polyadenylation machinery in the nucleus. The polyadenylation machinery consists of several factors, including cleavage factor I, cleavage and polyadenylation specificity factor, cleavage factor II, and cleavage stimulation factor. These complexes bind to specific sequences in mRNA 3′UTRs and facilitate the cleavage at a specific site downstream of the AAUAAA motif. This cleavage is aided by cleavage factor polyribonucleotide kinase subunit 1, followed by adding a polyadenylate tail to the mRNA molecule by the enzyme poly(A) polymerase alpha (Tian and Manley, 2013). A strong polyadenylation signal at the 3′UTR end is important for the efficient cleavage and polyadenylation of mRNAs. However, many genes also have additional polyadenylation signals at their 3′UTRs in eukaryotes, and the usage of these signals can be regulated through APA (Fig. 3A).
APA is a widespread phenomenon in metazoan protein-coding transcripts (70%-79% of mammalian genes). In humans, >70% of genes have more than one polyadenylation site in their 3′UTRs, and approximately 50% have three or more. By contrast, in the mouse liver, >60% of expressed genes had multiple polyadenylation signals in their 3′UTRs (Tian and Manley, 2013). This can result in mRNAs with different 3′UTR ends and different regulatory and functional properties (Mitschka and Mayr, 2022). 3′UTR shortening was proposed to increase mRNA stability by reducing the accessibility of mRNA degradation mechanisms, such as RBP- or miRNA-based degradation. Conversely, 3′UTR lengthening may increase the accessibility of miRNAs, decreasing mRNA stability and translation.
In addition to regulating mRNA stability APA can play a role in mRNA–protein interactions and protein localization via alternative 3′UTRs. For example, the APA of CD47 mRNA 3′UTR can affect the interaction with different protein complexes and thereby direct CD47 localization to either the plasma membrane (long 3′UTRs) or endoplasmic reticulum (short 3′UTRs) in various cancers (Berkovits and Mayr, 2015; Ma and Mayr, 2018). More studies are required to understand this interesting phenomenon by 3′UTR-directed protein localization.
AS in 3′UTRs
AS can also alter the 3′UTR length if 3′UTR contains an internal intron (Fig. 3B). It will increase the length, heterogeneity, and functional diversity of 3′UTRs (Bicknell et al., 2012; Chan et al., 2022b). The combination of APA and AS could further increase mRNA isoform variability resulting in the generation of mRNA transcripts containing various forms (Fig. 3C). The splicing of introns located within 3′UTRs was first described in heterogenous nuclear ribonucleoprotein D (hnRNPD/AUF1) (Wilson et al., 1999). This study reported that splicing of the intron in 3′UTR regulates AUF1 expression, so it may play a significant role in gene expression regulation.
Another study demonstrated that 3′UTRs of integrin subunit alpha 3 (ITGA3) mRNA interacts with muscleblind like splicing regulator 2 (MBNL2) in human lung carcinoma cells (Adereth et al., 2005; Pascual et al., 2006). These splicing factors regulate the AS of ITGA3 3′UTR, in which produces distinct 3′UTR variants with different functions. The authors also showed the ITGA3 mRNA localized to adhesion plaques, specialized structures involved in cell adhesion and signaling. Moreover, in the gene coding for an activity regulated cytoskeleton associated protein (Arc), AS generates isoforms with distinct 3′UTRs. The AS of Arc 3′UTR is induced by long-term potentiation learning and memory (Paolantoni et al., 2018).
The 3′UTR of the β-catenin gene CTNNB1 is also an interesting example. Three 3′UTR variants are expressed following the AS of an intron located within 3′UTRs (Chan et al., 2022b; Thiele et al., 2006). The expression of variant 3′UTRs in β-catenin mRNA was reported in peripheral blood mononuclear leukocytes (PBMCs). This suggests that different isoforms of β-catenin mRNAs may play different roles in regulating gene expression in PBMCs (Thiele et al., 2006). Recently, a pan-cancer analysis revealed pervasive upregulation of 3′UTR splicing driving tumorigenesis with b-catenin as a top-dysregulated 3′UTR (Chan et al., 2022b). Thus, 3′UTR diversity could not only contribute to the overall diversity of the transcriptome and proteome but also drive cancer development and progression.
3′UTR-MEDIATED DISEASES
Transcriptome analyses of human cancer databases revealed that a large percentage of genes in cancers have RNA alterations (PCAWG Transcriptome Core Group et al., 2020). RNA alterations are mostly in protein-coding regions, but 3′UTR diversity also attribute to RNA alterations. Because APA is widespread and alters the regulatory potential of 3′UTRs, APA dysregulation plays a significant role in cancers (Kahles et al., 2018). Global APA within 3′UTRs is involved in the proliferation and metastasis of cancer cells and tumor tissues (Hoque et al., 2013; Mayr and Bartel, 2009). APA dysregulation is exemplified in Cyclin D1 overexpression because of 3′UTR shortening (Mayr and Bartel, 2009; Wiestner et al., 2007). This 3′UTR shortening leads to the loss of binding sites of complementary miRNA to escape repression and potentially contribute to oncogene activation (Yang and Nam, 2020).
Based on genome and transcriptome databases, AS events in cancer tissues are estimated to be 20% higher on average than in normal tissues (Kahles et al., 2018). Recently, a pan-cancer analysis revealed that pervasive upregulation of 3′UTR splicing drives tumorigenesis (Chan et al., 2022b). In hepatocellular carcinoma, aberrant 3′UTR isoforms of β-catenin mRNA escape non-sense-mediated mRNA decay and promote cell proliferation and migration (Chan et al., 2022b). Thus, 3′UTR diversity could not only contribute to the overall complexity of the transcriptome and proteome but also drive cancer development and progression (Chan et al., 2022a).
As in cancer disorders of neuronal plasticity and learning, 3′UTRs appear to be a pathological hotspot (Conne et al., 2000). Because several neuronal mRNAs depend on their 3′UTRs for appropriate subcellular targeting or translational control, perturbations in 3′UTR-mediated functions deserve attention. In addition, alterations in the secondary structure of 3′UTRs are related to the pathology of a certain disease (Reamon-Buettner et al., 2007). Mutations in the 3′UTR of GATA binding protein 4 (GATA4) mRNA alter its secondary structure and may contribute to the development of congenital heart disease (Reamon-Buettner et al., 2007). Therefore, further studies could explain the mechanism of the 3′UTR-mediated disease development (Conne et al., 2000).
CONCLUSIONS AND PERSPECTIVES
As genomic and transcriptomic data accumulated, RNA alterations emerged as important features of cancer development (PCAWG Transcriptome Core Group et al., 2020). Among many RNA alterations, 3′UTR variants received little attention in comparison with those in protein-coding regions (Bicknell et al., 2012). However, a widespread shortening of 3′UTR lengths in cancers and causal UTR variants in human diseases demonstrated the important roles of 3′UTRs in disease development (Griesemer et al., 2021; Mayr and Bartel, 2009). 3′UTR alterations can contribute to the diversification of the transcriptome and protein functions, impacting numerous biological processes.
3′UTR activities are context- and condition-dependent, dynamically affecting gene expression programs by miRNAs, RBPs, and RNA granule formation. Thus, finding rules and factors generating and modulating 3′UTR variants, such as 3′-end processing machinery, 3′UTR-binding proteome and UTR-mediated RNP granules, might be important. As functional alterations in 3′UTRs are found in various diseases, a systemic search for “3′UTR-mediated diseases” will extend the horizons in the diagnosis and treatment of these diseases (Conne et al., 2000). Specifically, functional cis-regulatory elements in 3′UTRs in pathogenic genes, interaction with disease-associated RBPs, and their pathogenic conditions should be understood to elucidate the mechanism and their consequent phenotypic changes in diseases. It could also open exciting new research areas, answering the question of what enables the biological complexity in humans during evolution.
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