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Mol. Cells 2023; 46(1): 48-56

Published online January 20, 2023

https://doi.org/10.14348/molcells.2023.0003

© The Korean Society for Molecular and Cellular Biology

3’UTR Diversity: Expanding Repertoire of RNA Alterations in Human mRNAs

Dawon Hong and Sunjoo Jeong*

Author Info. +

Laboratory of RNA Cell Biology, Department of Bioconvergence Engineering, Dankook University Graduate School, Yongin 16892, Korea

Correspondence to : sjsj@dankook.ac.kr

Received: January 2, 2023; Revised: January 5, 2023; Accepted: January 8, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

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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 posttranscriptional 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.

Keywords 3′UTR diversity, alternative polyadenylation, alternative splicing, cancer, RNA alterations, transcriptome

INTRODUCTION

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In the nucleus, eukaryotic mRNA is synthesized from a gene in a 5′ to 3′ direction and processed into mature transcripts by 5′-capping, splicing, and 3′-end formation. Genomic information is translated to proteins once mature mRNAs are exported to the cytoplasm. 5′ and 3′ sequences flanking the coding regions are not translated, thus named as untranslated regions (UTRs). What are the roles of UTRs in regulating gene expression? 5′UTRs are the leading sites for ribosome assembly for mRNA translation. In contrast, 3′UTRs play various roles in the post-transcriptional control of gene expressions, including stability, translation, and subcellular localization of mRNAs (Mayr, 2019). We will begin by reviewing why 3′UTR diversity is important, especially in human mRNAs. This review focuses only on the length of 3′UTRs, but not on their sequences and modification, as 3′UTR diversity for simplicity.

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

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3′UTRs contain cis-regulatory elements recognized by trans-acting factors. 3′UTR-mediated mRNA metabolism controls at the steps of the stability, translation, and localization of mRNA (Fig. 2). 3′UTRs form ribonucleoprotein (RNP) with many RNA binding proteins (RBPs). So we will describe representative mRNA 3′UTRs, corresponding main RBPs, and their relevant functions as follows (Table 1).

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

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Considering the important roles of 3′UTRs in post-transcriptional gene expression, 3′UTR-mediated control should be regulated by many factors, including miRNA, RBPs and RNA granules as follows.

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

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3′UTR diversity can be caused by various ways, such as genetic variations, RNA modification, alternative cleavage, alternative polyadenylation (APA), and alternative splicing (AS). These could diversify the transcriptome and contribute to epigenetic gene regulation. This section focuses on the length-diversifying mechanism, APA, and AS (Fig. 3). Databases with different 3′UTR lengths formed by APA and AS are also summarized in Table 2.

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

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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

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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.

ACKNOWLEDGMENTS

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This work was supported by the National Research Foundation (NRF), funded by the Ministry of Science & ICT (NRF-2020R1A2C2005358 and NRF-2022M3E5F1016546).

FIGURES

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Fig. 1. Length and internal introns in untranslated region (UTR) during evolution. The average length of the 5′UTR and 3′UTR of mRNA among different organisms. The 5′UTR is typically shorter compared to the 3′UTR. In Homo sapiens, the average length of the 3′UTR is about 1030 nucleotides (nt), which is longer than the average length of the 3′UTR in other species. Percentage of genes containing internal introns is also shown in H. sapiens (8%) and other mammals (2%).
Fig. 2. Roles of 3′ untranslated region (3′UTR) in post-transcriptional regulation.. The diagram illustrates a typical mRNA structure consisting of 5′UTR, coding region, and 3′UTR. The 3′UTR is located following the stop codon and before the poly(A) tail. It includes cisregulatory elements like AU-rich elements (AREs), Alu elements and microRNA (miRNA) targets, and polyadenylation sites. The 3′UTRs play important roles in post-transcriptional gene regulation of mRNA stability, translation, and localization.
Fig. 3. Regulatory events generating 3′ untranslated region (3′UTR) length diversity. (A) Alternative polyadenylation (APA) in 3′UTR. The generation of 3′UTR length diversity using different cleavage and polyadenylation sites: proximal polyadenylation site (pPAS) and distal polyadenylation site (dPAS). The selection of pPAS over dPAS, or vice versa, can result in different 3′UTR lengths. If the pPAS is selected, the 3′UTR will be shorter (shown in the pink box); the dPAS is selected, the 3′UTR will be longer (shown in the pink box and red box). (B) Alternative splicing (AS) within 3′UTR. The generation of 3′UTR length diversity using the internal intron in 3′UTR (shown in the blue line). Inclusion or skipping of this intron can affect the length of the 3′UTR. If the intron is included, 3′UTR will contain an intronic sequence (shown in the blue box). (C) Combination of APA and AS events in 3′UTR. More 3'UTR variants can be generated.

TABLES

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Table 1.

List of representative mRNAs with 3’UTR-mediated control

TranscriptRNA-binding proteinsControlFunctionReference
HunchbackPumilio
Nanos
Brat		Translation repressionEmbryonic axis formation in Drosophila(Kuersten and Goodwin, 2003)
UCP1CPEB2Translation activationMaintain body temperature(Chen et al., 2018)
CaMK2AMubLocalization translationControl learning and memory in neuron(Broix et al., 2021; Chen et al., 2022)
ACTBIGF2BP1
PAT1		Stabilization local-translationConstituent of the cytoskeleton for structural support and movement in neuron(Wu et al., 2020)
OskarBruno
Hrp48		RNP granule formation
Translation		Embryonic patterning and germline formation in Drosophila(Bose et al., 2022; Jambor et al., 2014)
DMPKCUG-BP2mRNA export
Translation		Maintenance of the myelin sheath(Amack and Mahadevan, 2001; Taneja et al., 1995)
n-myc
c-fos		ELAV like RNA binding protein familyARE-mediated mRNA stabilizationCellular growth in neuroblastoma(Chagnovich and Cohn, 1996; Chagnovich et al., 1996)
P21WAF1SRSF3Translation repressionRegulator of cell cycle and senescence(Kim et al., 2022)
COX-2HuR
b-catenin		mRNA stabilization
Translation activation		Cellular proliferation and tumorigenesis(Kim et al., 2012; Lee and Jeong, 2006)

Table 2.

List of Database related to 3′UTR divers

Tool nameFeaturesURLReference
Poly(A) sites databases
PolyASite 2.0APA atlas made from 3′end sequencing datahttps://polyasite.unibas.ch(Herrmann et al., 2020)
PolyA_DB 3APA atlas built from ~1.2 billion 3′end deep sequencing readshttps://exon.apps.wistar.org/PolyA_DB/v3/(Wang et al., 2018)
scAPAdbAPA atlas at single-cell resolution from publications and Genomics websitehttp://www.bmibig.cn/scAPAdb/(Zhu et al., 2022)
TREND-DBAPA database constructed from bulk RNA-seq data of potential APA regulatorshttp://shiny.imbei.uni-mainz.de:3838/trend-db(Marini et al., 2021)
3′UTR alternative splicing databases
RNA structure databases3′UTR splicing events database from RNA-seq data of TCGA and GTExhttps://www.cbrc.kaust.edu.sa/spur/home/(Chan et al., 2022b)
RNA structure databases
RNAfoldPrediction tool of secondary structures for single-stranded RNA or DNAhttp://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi(Lorenz et al., 2011)

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Article

Minireview

Mol. Cells 2023; 46(1): 48-56

Published online January 31, 2023 https://doi.org/10.14348/molcells.2023.0003

Copyright © The Korean Society for Molecular and Cellular Biology.

3’UTR Diversity: Expanding Repertoire of RNA Alterations in Human mRNAs

Dawon Hong and Sunjoo Jeong*

Laboratory of RNA Cell Biology, Department of Bioconvergence Engineering, Dankook University Graduate School, Yongin 16892, Korea

Correspondence to:sjsj@dankook.ac.kr

Received: January 2, 2023; Revised: January 5, 2023; Accepted: January 8, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

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 posttranscriptional 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.

Keywords: 3′UTR diversity, alternative polyadenylation, alternative splicing, cancer, RNA alterations, transcriptome

INTRODUCTION

In the nucleus, eukaryotic mRNA is synthesized from a gene in a 5′ to 3′ direction and processed into mature transcripts by 5′-capping, splicing, and 3′-end formation. Genomic information is translated to proteins once mature mRNAs are exported to the cytoplasm. 5′ and 3′ sequences flanking the coding regions are not translated, thus named as untranslated regions (UTRs). What are the roles of UTRs in regulating gene expression? 5′UTRs are the leading sites for ribosome assembly for mRNA translation. In contrast, 3′UTRs play various roles in the post-transcriptional control of gene expressions, including stability, translation, and subcellular localization of mRNAs (Mayr, 2019). We will begin by reviewing why 3′UTR diversity is important, especially in human mRNAs. This review focuses only on the length of 3′UTRs, but not on their sequences and modification, as 3′UTR diversity for simplicity.

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

3′UTRs contain cis-regulatory elements recognized by trans-acting factors. 3′UTR-mediated mRNA metabolism controls at the steps of the stability, translation, and localization of mRNA (Fig. 2). 3′UTRs form ribonucleoprotein (RNP) with many RNA binding proteins (RBPs). So we will describe representative mRNA 3′UTRs, corresponding main RBPs, and their relevant functions as follows (Table 1).

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

Considering the important roles of 3′UTRs in post-transcriptional gene expression, 3′UTR-mediated control should be regulated by many factors, including miRNA, RBPs and RNA granules as follows.

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

3′UTR diversity can be caused by various ways, such as genetic variations, RNA modification, alternative cleavage, alternative polyadenylation (APA), and alternative splicing (AS). These could diversify the transcriptome and contribute to epigenetic gene regulation. This section focuses on the length-diversifying mechanism, APA, and AS (Fig. 3). Databases with different 3′UTR lengths formed by APA and AS are also summarized in Table 2.

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.

ACKNOWLEDGMENTS

This work was supported by the National Research Foundation (NRF), funded by the Ministry of Science & ICT (NRF-2020R1A2C2005358 and NRF-2022M3E5F1016546).

AUTHOR CONTRIBUTIONS

S.J. conceived the idea, wrote the manuscript, and secured funding. D.W. performed experiments and wrote the manuscript.

CONFLICT OF INTEREST

The authors have no potential conflicts of interest to disclose.

Figures

Go to
Fig. 1.Length and internal introns in untranslated region (UTR) during evolution. The average length of the 5′UTR and 3′UTR of mRNA among different organisms. The 5′UTR is typically shorter compared to the 3′UTR. In Homo sapiens, the average length of the 3′UTR is about 1030 nucleotides (nt), which is longer than the average length of the 3′UTR in other species. Percentage of genes containing internal introns is also shown in H. sapiens (8%) and other mammals (2%).
Fig. 2.Roles of 3′ untranslated region (3′UTR) in post-transcriptional regulation.. The diagram illustrates a typical mRNA structure consisting of 5′UTR, coding region, and 3′UTR. The 3′UTR is located following the stop codon and before the poly(A) tail. It includes cisregulatory elements like AU-rich elements (AREs), Alu elements and microRNA (miRNA) targets, and polyadenylation sites. The 3′UTRs play important roles in post-transcriptional gene regulation of mRNA stability, translation, and localization.
Fig. 3.Regulatory events generating 3′ untranslated region (3′UTR) length diversity. (A) Alternative polyadenylation (APA) in 3′UTR. The generation of 3′UTR length diversity using different cleavage and polyadenylation sites: proximal polyadenylation site (pPAS) and distal polyadenylation site (dPAS). The selection of pPAS over dPAS, or vice versa, can result in different 3′UTR lengths. If the pPAS is selected, the 3′UTR will be shorter (shown in the pink box); the dPAS is selected, the 3′UTR will be longer (shown in the pink box and red box). (B) Alternative splicing (AS) within 3′UTR. The generation of 3′UTR length diversity using the internal intron in 3′UTR (shown in the blue line). Inclusion or skipping of this intron can affect the length of the 3′UTR. If the intron is included, 3′UTR will contain an intronic sequence (shown in the blue box). (C) Combination of APA and AS events in 3′UTR. More 3'UTR variants can be generated.

Tables

List of representative mRNAs with 3’UTR-mediated control

Transcript RNA-binding proteins Control Function Reference
Hunchback Pumilio
Nanos
Brat		 Translation repression Embryonic axis formation in Drosophila (Kuersten and Goodwin, 2003)
UCP1 CPEB2 Translation activation Maintain body temperature (Chen et al., 2018)
CaMK2A Mub Localization translation Control learning and memory in neuron (Broix et al., 2021; Chen et al., 2022)
ACTB IGF2BP1
PAT1		 Stabilization local-translation Constituent of the cytoskeleton for structural support and movement in neuron (Wu et al., 2020)
Oskar Bruno
Hrp48		 RNP granule formation
Translation		 Embryonic patterning and germline formation in Drosophila (Bose et al., 2022; Jambor et al., 2014)
DMPK CUG-BP2 mRNA export
Translation		 Maintenance of the myelin sheath (Amack and Mahadevan, 2001; Taneja et al., 1995)
n-myc
c-fos		 ELAV like RNA binding protein family ARE-mediated mRNA stabilization Cellular growth in neuroblastoma (Chagnovich and Cohn, 1996; Chagnovich et al., 1996)
P21WAF1 SRSF3 Translation repression Regulator of cell cycle and senescence (Kim et al., 2022)
COX-2 HuR
b-catenin		 mRNA stabilization
Translation activation		 Cellular proliferation and tumorigenesis (Kim et al., 2012; Lee and Jeong, 2006)

List of Database related to 3′UTR divers

Tool name Features URL Reference
Poly(A) sites databases
PolyASite 2.0 APA atlas made from 3′end sequencing data https://polyasite.unibas.ch (Herrmann et al., 2020)
PolyA_DB 3 APA atlas built from ~1.2 billion 3′end deep sequencing reads https://exon.apps.wistar.org/PolyA_DB/v3/ (Wang et al., 2018)
scAPAdb APA atlas at single-cell resolution from publications and Genomics website http://www.bmibig.cn/scAPAdb/ (Zhu et al., 2022)
TREND-DB APA database constructed from bulk RNA-seq data of potential APA regulators http://shiny.imbei.uni-mainz.de:3838/trend-db (Marini et al., 2021)
3′UTR alternative splicing databases
RNA structure databases 3′UTR splicing events database from RNA-seq data of TCGA and GTEx https://www.cbrc.kaust.edu.sa/spur/home/ (Chan et al., 2022b)
RNA structure databases
RNAfold Prediction tool of secondary structures for single-stranded RNA or DNA http://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi (Lorenz et al., 2011)

Fig 1.

Download
Figure 1.Length and internal introns in untranslated region (UTR) during evolution. The average length of the 5′UTR and 3′UTR of mRNA among different organisms. The 5′UTR is typically shorter compared to the 3′UTR. In Homo sapiens, the average length of the 3′UTR is about 1030 nucleotides (nt), which is longer than the average length of the 3′UTR in other species. Percentage of genes containing internal introns is also shown in H. sapiens (8%) and other mammals (2%).
Molecules and Cells 2023; 46: 48-56https://doi.org/10.14348/molcells.2023.0003

Fig 2.

Download
Figure 2.Roles of 3′ untranslated region (3′UTR) in post-transcriptional regulation.. The diagram illustrates a typical mRNA structure consisting of 5′UTR, coding region, and 3′UTR. The 3′UTR is located following the stop codon and before the poly(A) tail. It includes cisregulatory elements like AU-rich elements (AREs), Alu elements and microRNA (miRNA) targets, and polyadenylation sites. The 3′UTRs play important roles in post-transcriptional gene regulation of mRNA stability, translation, and localization.
Molecules and Cells 2023; 46: 48-56https://doi.org/10.14348/molcells.2023.0003

Fig 3.

Download
Figure 3.Regulatory events generating 3′ untranslated region (3′UTR) length diversity. (A) Alternative polyadenylation (APA) in 3′UTR. The generation of 3′UTR length diversity using different cleavage and polyadenylation sites: proximal polyadenylation site (pPAS) and distal polyadenylation site (dPAS). The selection of pPAS over dPAS, or vice versa, can result in different 3′UTR lengths. If the pPAS is selected, the 3′UTR will be shorter (shown in the pink box); the dPAS is selected, the 3′UTR will be longer (shown in the pink box and red box). (B) Alternative splicing (AS) within 3′UTR. The generation of 3′UTR length diversity using the internal intron in 3′UTR (shown in the blue line). Inclusion or skipping of this intron can affect the length of the 3′UTR. If the intron is included, 3′UTR will contain an intronic sequence (shown in the blue box). (C) Combination of APA and AS events in 3′UTR. More 3'UTR variants can be generated.
Molecules and Cells 2023; 46: 48-56https://doi.org/10.14348/molcells.2023.0003

. List of representative mRNAs with 3’UTR-mediated control.

TranscriptRNA-binding proteinsControlFunctionReference
HunchbackPumilio
Nanos
Brat		Translation repressionEmbryonic axis formation in Drosophila(Kuersten and Goodwin, 2003)
UCP1CPEB2Translation activationMaintain body temperature(Chen et al., 2018)
CaMK2AMubLocalization translationControl learning and memory in neuron(Broix et al., 2021; Chen et al., 2022)
ACTBIGF2BP1
PAT1		Stabilization local-translationConstituent of the cytoskeleton for structural support and movement in neuron(Wu et al., 2020)
OskarBruno
Hrp48		RNP granule formation
Translation		Embryonic patterning and germline formation in Drosophila(Bose et al., 2022; Jambor et al., 2014)
DMPKCUG-BP2mRNA export
Translation		Maintenance of the myelin sheath(Amack and Mahadevan, 2001; Taneja et al., 1995)
n-myc
c-fos		ELAV like RNA binding protein familyARE-mediated mRNA stabilizationCellular growth in neuroblastoma(Chagnovich and Cohn, 1996; Chagnovich et al., 1996)
P21WAF1SRSF3Translation repressionRegulator of cell cycle and senescence(Kim et al., 2022)
COX-2HuR
b-catenin		mRNA stabilization
Translation activation		Cellular proliferation and tumorigenesis(Kim et al., 2012; Lee and Jeong, 2006)

. List of Database related to 3′UTR divers.

Tool nameFeaturesURLReference
Poly(A) sites databases
PolyASite 2.0APA atlas made from 3′end sequencing datahttps://polyasite.unibas.ch(Herrmann et al., 2020)
PolyA_DB 3APA atlas built from ~1.2 billion 3′end deep sequencing readshttps://exon.apps.wistar.org/PolyA_DB/v3/(Wang et al., 2018)
scAPAdbAPA atlas at single-cell resolution from publications and Genomics websitehttp://www.bmibig.cn/scAPAdb/(Zhu et al., 2022)
TREND-DBAPA database constructed from bulk RNA-seq data of potential APA regulatorshttp://shiny.imbei.uni-mainz.de:3838/trend-db(Marini et al., 2021)
3′UTR alternative splicing databases
RNA structure databases3′UTR splicing events database from RNA-seq data of TCGA and GTExhttps://www.cbrc.kaust.edu.sa/spur/home/(Chan et al., 2022b)
RNA structure databases
RNAfoldPrediction tool of secondary structures for single-stranded RNA or DNAhttp://rna.tbi.univie.ac.at/cgi-bin/RNAWebSuite/RNAfold.cgi(Lorenz et al., 2011)

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Mol. Cells
Mar 31, 2023 Vol.46 No.3, pp. 131~189
COVER PICTURE
The physiologically important cytoprotective signaling in normal cells (background area in turquoise) mediated by NRF2 (blue chain) is often hijacked by cancer cells (red ball) in the tumor microenvironment (yellow area). However, the differential roles of NRF2 throughout the multistage carcinogenesis remains largely unresolved (white-colored overlapping misty areas).
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