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Open Access 01.12.2021 | Review

Crosstalk between N6-methyladenosine modification and circular RNAs: current understanding and future directions

verfasst von: Xin Wang, Rui Ma, Xilin Zhang, Lian Cui, Yangfeng Ding, Weimin Shi, Chunyuan Guo, Yuling Shi

Erschienen in: Molecular Cancer | Ausgabe 1/2021

Abstract

N⁶-methyladenosine (m⁶A) is a prevalent internal modification in eukaryotic RNAs regulated by the so-called “writers”, “erasers”, and “readers”. m⁶A has been demonstrated to exert critical molecular functions in modulating RNA maturation, localization, translation and metabolism, thus playing an essential role in cellular, developmental, and disease processes. Circular RNAs (circRNAs) are a class of non-coding RNAs with covalently closed single-stranded structures generated by back-splicing. CircRNAs also participate in physiological and pathological processes through unique mechanisms. Despite their discovery several years ago, m⁶A and circRNAs has drawn increased research interest due to advances in molecular biology techniques these years. Recently, several scholars have investigated the crosstalk between m⁶A and circRNAs. In this review, we provide an overview of the current knowledge of m⁶A and circRNAs, as well as summarize the crosstalk between these molecules based on existing research. In addition, we present some suggestions for future research perspectives.

Xin Wang, Rui Ma and Xilin Zhang contributed equally to this work.

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m6A

N6-methyladenosine

circRNAs

Circular RNAs

MTC

Methyltransferases complex

METTL3

Methyltransferase-like 3

METTL14

Methyltransferase-like 14

METTL5

Methyltransferase-like 5

METTL16

Methyltransferase-like 16

HAKAI

Cbl proto-oncogene-like 1

WTAP

Wilms’ tumor 1-associating protein

VIRMA

Vir Like M6A Methyltransferase Associated

RBM15/15B

RNA Binding Motif Protein 15/15B;

ZCCHC4

Zinc Finger CCCH-Type Containing 4

ZC3H13

Zinc Finger CCCH-Type Containing 13

FTO

Fat mass and obesity-associated protein

ALKBH5

AlkB homolog 5

YTH

YT521-B homology

HNRNP

Heterogeneous nuclear ribonucleoprotein

IGF2BPs

Insulin-like growth factor 2 mRNA-binding proteins

EIF3

Eukaryotic translation initiation factor 3

PRRC2A

Proline rich coiled-coil 2A

SND1

Staphylococcal nuclease and tudor domain containing 1

RBPs

RNA binding proteins

carRNAs

Chromosome-associated regulatory RNAs

pri-miRNAs

primary miRNAs

ELAVL1

ELAV like RNA binding protein 1

MATR3

Matrin 3

PABPC1

Poly(A) binding protein cytoplasmic 1

UTR

Untranslated region

eIF3h

Eukaryotic translation initiation factor 3 subunit h

EcRNAs

Exonic circRNAs

EIcRNAs

Exon-intron circRNAs

ciRNAs

Intronic circRNAs

MeCP2

Methyl CpG binding protein 2

ceRNA

Competing endogenous RNA

IRES

Internal ribosome entry site

Ago2

Argonaute 2

RISC

RNA-induced silencing complex

Background

RNA modifications (e.g., N⁶-methyladenosine [m⁶A], 5-methylcytosine, pseudouridine, N⁴-acetylcytidine, ribose methylations, and N¹-methylguanosine), have recently emerged as vital post-transcriptional epigenetic modulators of gene expression in eukaryotes [1, 2]. Among these RNA modifications, m⁶A represents the most common and well-studied to date. m⁶A is a reversible modification that methylated adenosine at the N⁶ position of almost every type of RNA molecule, including mRNAs, small nuclear RNAs, ribosomal RNAs, and non-coding RNAs [1‐3]. m⁶A was first discovered in the 1970s and developed rapidly during the past few years due to the advances in high-throughput m⁶A sequencing and methylated RNA m⁶A immunoprecipitation [4]. Moreover, m⁶A has been demonstrated to exert critical molecular functions in modulating RNA maturation, localization, translation, and metabolism. m⁶A dynamically exists and is involved in a variety of physiological and pathological processes, including growth, development, aging and diseases [4‐6].

Circular RNAs (circRNAs) are a class of endogenous RNAs with covalently closed single-stranded structures also present in eukaryotes [7, 8]. Most circRNAs are non-coding RNAs while a proportion of cytoplasmic circRNAs have the coding potential to be translated into peptides [9, 10]. These molecules were also discovered several years ago, but has recently attracted the attention of researchers due to the advances in high-throughput RNA sequencing and bioinformatics [11]. Similar to other types of RNAs, circRNAs are involved in the maintenance of the normal physiological function of the human body, as well as the occurrence and development of a variety of human diseases [11‐13]. While distinct from other RNA molecules, circRNAs possess unique biogenesis, biology, and characterization. Therefore, they may present peculiarities in response to RNA modifications.

Recently, some scholars have combined these two recent hot topics to investigate the crosstalk between them. In this review, we provide an overview of the current knowledge of m⁶A as well as circRNAs, and summarize the crosstalk between m⁶A modification and circular RNAs based on existing research. In addition, we have found that many questions still remain unanswered in this area and present some suggestions for future research perspectives.

RNA m⁶A modification

Similar to DNA methylation, RNA m⁶A methylation is catalyzed and recognized by corresponding enzymes, methyltransferases- “writers”, demethylases- “erasers” and “readers”. Subsequently, these modified RNAs will present with a different fate in maturation, localization, translation and metabolism, thereby influencing various molecular cellular processes. The specific details are described below and a summary is presented in Fig. 1.

Participants of m⁶A modification: writers, erasers, and readers

m⁶A writers

The m⁶A is installed by the multicomponent m⁶A methyltransferases complex (MTC), known as “writers”. The currently reported writers include methyltransferase-like 3 (METTL3), methyltransferase-like 14 (METTL14), methyltransferase-like 5 (METTL5), methyltransferase-like 16 (METTL16), Cbl proto-oncogene-like 1 (HAKAI), Wilms’ tumor 1-associating protein (WTAP), Vir Like M⁶A Methyltransferase Associated (VIRMA), RNA Binding Motif Protein 15/15B (RBM15/15B), Zinc Finger CCCH-Type Containing 4 (ZCCHC4), and Zinc Finger CCCH-Type Containing 13 (ZC3H13). These enzymes perform their respective duties and jointly complete the “writing” task. According to current knowledge, METTL3, METTL5, and METTL16 function as catalytic cores in the complex which catalyze m⁶A modification via methyltransferase domains [3‐5, 14‐16]. Other components typically play auxiliary roles, such as structural stabilization, reorganization of special RNA sites, and directing MTC location [3‐5, 14‐16].

m⁶A erasers

The m⁶A installed by writers can be removed by demethylases, or so-called “erasers”, which include fat mass and obesity-associated protein (FTO) and AlkB homolog 5 (ALKBH5) [14‐16]. These two demethylases are localized in nuclear speckles and can oxidatively eliminate both DNA and RNA methylation, with a particularity for m⁶A methylation [15‐17]. The identification of m⁶A demethylation provides evidence for the possible reversibility of the m⁶A modification.

m⁶A readers

To exert their biological functions, the m⁶A modifications determined by m⁶A writers and erasers must be identified by m⁶A readers. The currently reported readers include the YT521-B homology (YTH) domain family proteins (YTHDF1, YTHDF2, and YTHDF3), YTH domain containing proteins (YTHDC1 and YTHDC2), heterogeneous nuclear ribonucleoprotein (HNRNPC, HNRNPG, and HNRNPA2B1), insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1, IGF2BP2, IGF2BP3), eukaryotic translation initiation factor 3 (EIF3), proline rich coiled-coil 2A (PRRC2A), and staphylococcal nuclease and tudor domain containing 1 (SND1). These RNA binding proteins (RBPs) have conserved m⁶A-binding domains that can specifically recognize m⁶A modifications. RBPs bind to m⁶A methylated RNAs and determine the fate of these RNAs, thus regulating various cellular processes such as transcription, splicing and maturing, exportation, translation, decay and others [3‐5, 14‐16]. Therefore, the m⁶A readers represent intermediaries for RNA m⁶A modification and different RNA fates.

A more comprehensive summary than previous reviews on the classification and functions of m⁶A writers, erasers, and readers is presented in Table 1. It appears that compared with a simple m⁶A installation and elimination function of writers and erasers, the roles of readers are more complicated and diverse, which is an area of keen research interest.

Table 1

Writers, erasers and readers of RNA m⁶A modification

Category	Factors	Roles	Refs
Writers	METTL3	m⁶A catalytic subunit	[14, 15]
	METTL14	Forms heterodimer with METTL3 to stabilize METTL3 and assist recognizing the subtract	[14, 18]
	METTL16	m⁶A catalytic subunit	[19]
	METTL5	Ribosome 18S m⁶A methyltransferase	[20, 21]
	TRMT112	Forms heterodimeric complex with METTL5 as a methyltransferase activator to stabilize METTL5	[21]
	ZCCHC4	Ribosome 28S m⁶A methyltransferase	[22, 23]
	HAKAI	Essential member of the MTC	[24]
	WTAP	Promotse m⁶A methyltransferase activity and localization in nuclear speckles	[25]
	VIRMA	Binds the MTC and recruit it to specific RNA region	[26]
	RBM15/15B	Binds the MTC and recruit it to specific RNA site	[27]
	ZC3H13	Promotes nuclear localization of MTC to modulate m⁶A in the nucleus	[28]
Erasers	FTO	Eliminates m⁶A by oxidation	[14‐18]
	ALKBH5	Eliminates m⁶A by oxidation	[14‐18]
Readers	YTHDF1	Facilitates the ribosome assembly of m⁶A-mRNAs and interacts with the initiation factor to promote translation; cooperates with YTHDF2 and YTHDF3 to mediate degradation of m⁶A-mRNAs	[29, 30]
	YTHDF2	Reduces m⁶A-mRNAs stability; stabilize m⁶A-mRNAs specifically in cancer stem cells; cooperates with YTHDF1 and YTHDF3 to mediate degradation of m⁶A-mRNAs	[29‐31]
	YTHDF3	Cooperates with YTHDF1 and YTHDF2 to mediate degradation of m⁶A-mRNAs	[30, 32]
	YTHDC1	Promotes RNA splicing and translocation; facilitates the decay of m⁶A-modified chromosome-associated regulatory RNAs; together with its target m⁶A-RNAs to regulate chromatin modification and retrotransposon repression; regulate histone methylation	[33‐38]
	YTHDC2	Facilitates the translation and decrease the abundance of m⁶A-RNAs; has 3′-5′ RNA helicase activity and decrease the stability of m⁶A-mRNAs	[39‐41]
	HNRNPC/G	Responsible for pre-mRNA processing and affect the alternative splicing of target m⁶A-mRNAs	[42‐44]
	HNRNPA2B1	Binds to m⁶A-containing pri-miRNAs to promote pri-miRNA processing; may regulate mRNA splicing by binding to m⁶A-containing pre-mRNAs; facilitates m⁶A modification and nucleocytoplasmic trafficking of mRNAs	[45, 46]
	IGF2BP1/2/3	Regulates m⁶A-RNAs stability, subcellular localization and translation	[47‐49]
	EIF3	Facilitates translation of m⁶A-mRNAs by recruiting the 43S complex	[50, 51]
	PRRC2A	Enhances m⁶A-mRNAs stability	[52]
	SND1	Enhances m⁶A-RNAs stability	[53]

Biological functions of m⁶A modification

The modulation of m⁶A methylation on RNAs begins during transcription and is largely dependent on the subcellular localization of writers, erasers, and readers. The writers are primarily localized in the nucleus, so the writing processes predominantly occur during the nuclear phase [14‐18]. The eraser ALKBH5 mainly exists and functions as a demethylase in the nucleus, and the eraser FTO exerts demethylase activity both in nucleus and cytoplasm [14‐18, 54]. Thus, the erasing processes may occur in the nucleus and cytoplasm. Some readers are localized and “read” m⁶A in the nucleus, which may influence nuclear processes, such as transcription and RNA splicing. In addition, some readers are able to assist with m⁶A-RNAs export from the nucleus to the cytoplasm. Readers in the cytoplasm may regulate cytosolic processes, such as translation and degradation.

m⁶A modulates RNA transcription, splicing, and structure

RNA m⁶A modification is a post-transcriptional regulation which appears not to be related to transcription; however, a recent study demonstrated that m⁶A modification on chromosome-associated regulatory RNAs (carRNAs), including promoter-associated RNAs, enhancer RNAs, and repeat RNAs, can induce carRNA decay by YTHDC1 and impact the open chromatin state and downstream transcription [36]. Moreover, RNA m⁶A modification play a critical role in transcription termination by facilitating the formation of co-transcriptional R-loops to decrease the readthrough activity of Pol II [55]. Reports have confirmed that m⁶A modification on primary miRNAs (pri-miRNAs) promotes the recognition and processing by the microRNA microprocessor complex protein, DGCR8, thereby enhancing miRNA maturation [45, 56]. The regulation of m⁶A on pre-mRNA splicing has been validated in Drosophila [57], whereas the precise regulation pattern remains largely unknown in mammals. Nevertheless, some efforts have been made to consummate the pathways through which m⁶A modulates pre-mRNA splicing in mammals. For example, the m⁶A reader, HNRNPG, may use Arg-Gly-Gly motifs to co-transcriptionally interact with RNA polymerase II and m⁶A-modified nascent pre-mRNA to modulate alternative splicing [44]. Additionally, YTHDC1 can recruit and promote pre-mRNA splicing factors to enter the binding regions of targeted mRNAs to modulate mRNA splicing [33]. In addition, the m⁶A modification on U2 and U6 snRNAs may influence the splicing of specific pre-mRNA transcripts [58, 59]. Evidence also shows that m⁶A can alter RNA structures to affect RNA-protein interactions in cells. For instance, m⁶A alters the local structure in mRNA and lncRNA and thereby influences the binding of HNRNPC to mediate pre-mRNA processing [42]. m⁶A located near splice sites in nascent pre-mRNA modulates HNRNPG binding, which influences RNAPII occupancy patterns and promotes HNRNPG-mediated alternative splicing [43, 44].

m⁶A modulates RNA subcellular localization

Mature RNAs modified by m⁶A in the nucleus are recognized by readers, which subsequently mediate subcellular localization. In general, nuclear readers (e.g., YTHDC1 and HNRNPA2B1) can identify m⁶A-RNAs (e.g., mRNAs and circRNAs), and accelerate their exportation from the nucleus to the cytoplasm [34, 45, 60]. However, for some RNAs, m⁶A modification may detain them within the nucleus. For example, m⁶A modification of lncRNA RP11 can increase its accumulation in the nucleus and on chromatin, which may be due to its interaction with HNRNPA2B1 [61]. Interestingly, several RNAs without m⁶A modification can still be exported from the nucleus, indicating that the m⁶A is a facilitator but not an indispensable factor for translocation [14].

m⁶A modulates RNA stability, translation, and binding capacity

RNA exported to the cytoplasm may exert their biological functions or be degraded, and m⁶A modification can impact these processes via multiple cytoplasmic readers. Readers mediate the degradation of m⁶A-mRNAs, including YTHDF1, YTHDF2, YTHDF3, and YTHDC2, and readers enhance m⁶A-mRNA stability, including IGF2BPs, PRRC2A, and SND1 (Table 1) [29‐32, 39‐41, 47, 52, 53]. Moreover, these readers may regulate RNA stability through diverse mechanisms. For example, the carboxy-terminal domain of YTHDF2 selectively interacts with m⁶A-mRNAs, whereas the amino-terminal domain mediates the transposition of the YTHDF2-mRNA complex from the translatable pool to mRNA decay sites (e.g., processing bodies) [62]. IGF2BPs probably recruit RNA stabilizers, such as ELAV like RNA binding protein 1 (ELAVL1 or HuR), matrin 3 (MATR3), and poly(A) binding protein cytoplasmic 1 (PABPC1), to maintain the stability of their target m⁶A-RNAs [47]. Numerous studies have demonstrated that m⁶A can regulate translation with the assistance of readers, including YTHDF1, YTHDF2, YTHDF3, YTHDC2, IGF2BPs, and EIF3 [29‐32, 39‐41, 47‐49], which involves several distinct mechanisms. For example, YTHDF1 can facilitate the ribosome assembly of m⁶A-mRNAs and interact with the initiation factor to promote translation [29]. In the absence of the cap-binding factor eIF4E, EIF3 can directly bind to the m⁶A in the 5′ untranslated region (UTR) and recruit the 43S complex to initiate translation [50]. METTL3 directly binds to the eukaryotic translation initiation factor 3 subunit h (eIF3h) and presumably promotes translation through ribosome recycling [63]. Promoter-bound METTL3 induces m⁶A in the coding region of mRNA to enhance translation by relieving ribosome stalling [64]. Moreover, m⁶A on 18S and 28S ribosomal RNA also play critical roles in the maintenance of ribosomal translation dynamics [20, 22]. Apart from the influence of the RNA-RBP interaction described above, m⁶A may also be indispensable for some RNA-RNA interactions. For example, the sufficient enrichment of the m⁶A modification on linc1281 is required for the interaction between linc1281 with miRNAs [65], and the m⁶A modified 353–357 region in the YAP 3’UTR was found to be critical for miR-582-3p targeting [66].

CircRNAs

In contrast to other RNA molecules, circRNAs have a unique circular structure, which requires a unique biogenesis process. Moreover, this stable structure may endow them with distinctive cellular functions, as well as unique approach to degradation. The associated details are described below and a summary is presented in Fig. 2.

Biogenesis of circRNAs

Similar to mRNA maturation, the biogenesis of circRNAs should also undergo processes, including the transcription and splicing of pre-mRNAs [7, 8, 11]. Therefore, the factors that regulate transcription (e.g., epigenetic modifications and transcription factors) may influence the generation of circRNAs [7, 8, 11]. Distinguished from the canonical splicing of mRNAs, the alternative splicing of circRNAs represents a unique mode that competes with mRNA splicing. Instead of the 5′-capping, 3′-polyadenylation and introns removing events of mRNA maturation, a downstream 5′-splice site and a 3′-splice site are connected to form a covalently closed single-stranded structure in circRNA splicing [7, 8, 11‐13]. There are several acknowledged mechanisms that can be used to interpret the circularization of circRNAs [7, 13, 67]. The first is intron pairing-driven circularization, in which the flanking of inverted repeat elements form RNA double strands through base-pairing. Another model is RBP-mediated circularization, in which the RBPs bind to the upstream and downstream flanking introns to form dimers. The third is lariat-driven circularization, which is mediated by the lariat structures that form in the exon-skipping events during linear splicing or intronic lariats that escape from the debranching of canonical linear splicing. These regulatory modes serve to bring the downstream splice-donor sites into close proximity with the upstream splice-acceptor site subject to alternative splicing. Based on the involved splicing and the genomic elements, three types of circRNAs are generated: 1) exonic circRNAs (EcRNAs), which are composed by one or more exons; 2) exon-intron circRNAs (EIcRNAs) that contain both exon and intron components; and 3) intronic circRNAs (ciRNAs), which consist of only introns [11, 68, 69].

Exportation and distribution of circRNAs

As described above, the biogenesis of circRNAs occurs in the nucleus, and are then exported to the cytoplasm or detained in the nucleus. In general, most circRNAs are exported into the cytoplasm and the vast majority of cytoplasmic circRNAs are EcRNAs without introns [7, 12, 13]. Similar to many linear RNAs, circRNAs involving intron elements (e.g., EIcRNAs and ciRNAs) are usually sequestered in the nucleus [7, 12, 13]. There are some underlying mechanisms may interpret the exportation and distribution of circRNAs. The first and the most recently concerned is m⁶A-mediated circRNA translocation, which will be discussed in detail below. Another mechanism is the length-dependent evolutionarily conserved pathway which involves the association of circRNA lengths with the conserved proteins, UAP56 and URH49 [70]. In addition, since circRNAs are also enriched and stable in exosomes, they also widely exist in extracellular components [71, 72].

Biological functions of circRNAs

Based on the unique characteristics and distribution, circRNAs may exert various biological functions. CircRNAs enriched in the nucleus are more likely to modulate transcription and splicing and several underlying mechanisms have been reported. For instance, circSCMH1 may interact with transcription factor methyl CpG binding protein 2 (MeCP2) to restrain its transcriptional activity [73]. circMRPS35 can recruit the histone acetyltransferase, KAT7, to elicit the acetylation of H4K5 in the promoters and directly bind to the promoters of FOXO1 and FOXO3a genes to activate the transcription [74]. CircRNAs derived from exon 6 of the SEP3 gene in Arabidopsis can bind to its cognate DNA locus to form an RNA:DNA hybrid, pausing transcription and exon 6 skipping in the alternative splicing of SEP3 pre-mRNA [75].

Compared with nuclear circRNAs, cytoplasmic circRNAs are better acquainted. The most frequently reported function of circRNAs is their capacity to act as miRNA sponges. Such sponging refers to the manner by which circRNAs impair miRNA activity through sequestration in a competing endogenous RNA (ceRNA) manner, thereby raising the expression of miRNA target genes [76, 77]. Compared with this explicit inhibitory role on miRNA, circRNAs exhibit diverse binding effects on various proteins [78‐81]. For example, circRNAs may not only recruit RBPs to stabilize and translate mRNAs, but also competitively bind to these RBPs to inhibit translation and degradation [62, 82, 83]. In addition, the interaction between RBPs and circRNAs may also influence the functionality and induce degradation through the ubiquitination of RBPs [84, 85].

CircRNAs are once considered as non-coding RNAs, however, recent studies have demonstrated that some cytoplasmic circRNAs carrying an initiation codon and putative open reading frames can be translated into peptides. Although lacking the traditional initiation elements (e.g., 5′ and 3’untranslated regions), circRNAs carrying an internal ribosome entry site (IRES) may undergo translation in a cap-independent manner [9, 86]. In addition, some circRNAs possess m⁶A and translation initiation sites may also go through m⁶A-driven translation with the assistance of the initiation factor, eIF4G2, and m⁶A reader, YTHDF3 [87]. Due to the same ORF components, several peptides translated by circRNAs are closely related to the proteins translated by their corresponding mRNAs. These peptides may act as substitutes to protect intact proteins from degradation or function as competitors to compete for regulators with intact proteins [88‐90]. As proteins, while they may also play other functions [91‐93], there are few relevant published studies, and further explorations remain to be performed.

Based on abundance and stability, circRNAs located in exosomes can be detected in the circulation and urine. Accumulating studies have confirmed that the circRNA content in the exosomes of some diseases is anomalous, indicating that they are promising diagnostic molecular markers [71, 72]. It is also feasible that cells transfer circRNAs to other cells or even throughout the body via excretion in exosomes. Therefore, they may act as mediators to ensure natural cell-to-cell communications. Besides, exosomes may bring abnormal amount of circRNAs to target cells, which is also an important source of various pathophysiological processes [71, 72].

Degradation of circRNAs

Although the structure is highly stable and are resistant to exonucleases [7, 8, 11], they will eventually be degraded through the involvement of several unique and diverse degradation pathways. The binding of miRNAs to circRNAs can initiate the Argonaute 2 (Ago2)-mediated RNA decay, which is executed by the RNA-induced silencing complex (RISC) [94]. However, this phenomenon may not be as common as expected since similar to linear RNAs, the overwhelming majority of circRNAs bear sequences that are only partially complementary to miRNAs [13]. CircRNAs modified by m⁶A may be decayed by the ribonuclease complex RNase P/MRP, which will be discussed in detail below. In addition, there is a structure-mediated RNA decay model (e.g., high overall 3′ UTR structure) formed by base pairing in circRNAs that can be targeted and degraded by UPF1 and G3BP1 [95]. Upon viral infection, circRNAs can also be globally degraded by activated RNase L, which is required for PKR activation [96]. Actually, the above-mentioned degradation pathways are also suitable for some other RNA molecules and not unique to circRNAs.

Crosstalk between m⁶A and circular RNAs

Through the above summary, we can find that there are many intersections between the regulatory pathway of m⁶A and the life cycle of circRNAs. Indeed, there have been many studies focusing on the crosstalk between m⁶A and circRNAs. Details are described below and a summary is shown in Table 2 and Fig. 3.

Table 2

Crosstalk between m⁶A and circRNAs

Crosstalk	circRNA	Roles	Refs
m⁶A regulates circRNAs expression	circMETTL3	METTL3 facilitates circMETTL3 expression in an m⁶A-dependent manner	[97]
	circ1662	METTL3 induced circ1662 generation by binding its flanking sequences and installing m⁶A modifications	[98]
	circCUX1	METTL3 mediates the m⁶A methylation of circCUX1 and stabilizes circCUX1	[99]
	circRNA-SORE	m⁶A modification raises circRNA-SORE level by increasing RNA stability	[100]
	circRNAs	m⁶A modification cause circRNAs selectively degraded by RNase P/MRP complex	[101]
m⁶A regulates circRNAs distribution	circGFRα1	METTL14 promotes cytoplasmic export of m⁶A-modified circGFRα1 through the GGACU motif	[102]
m⁶A regulates circRNAs distribution	circNSUN2	m⁶A modification of circNSUN2 facilitates cytoplasmic export	[60]
m⁶A regulates circRNAs function	circRNAs	Extensive m⁶A modifications in circRNAs drives protein translation in a cap-independent fashion	[87]
m⁶A regulates circRNAs function	circRNAs	m⁶A modification controls circRNA immunity	[103]
circRNAs regulate m⁶A	hsa_circ_0072309	hsa_circ_0072309 upregulates the expression of m⁶A demethylase FTO by targeting miR-607	[104]
	circMAP2K4	circMAP2K4 promote YTHDF1 expression by binding with hsa-miR-139-5p	[105]
	circRAB11FIP1	circRAB11FIP1 regulated the m⁶A methylation of ATG5 and ATG7 mRNA via upregulating FTO	[106]
	circMEG3	circMEG3 inhibits the expression of METTL3 dependent on HULC	[107]
	circNOTCH1	circNOTCH1 regulates the m⁶A modification on Nothch1 mRNA by binding to METTL14.	[108]
	circZbtb20	circZbtb20 enhances the interaction of ALKBH5 with Nr4a1 mRNA, leading to ablation of the m⁶A on Nr4a1 mRNA	[109]
	circSTAG1	circSTAG1 regulates m⁶A modification on FAAH by mediating ALKBH5 translocation	[110]

m⁶A modulates the expression of circRNAs

Similar to other RNA molecules, m⁶A can also modulate the expression of circRNAs through regulating their generation, stability, or degradation. A recent study confirmed that METTL3 can install m⁶A in the reverse complementary sequences of flanking introns of circ1662, as well as facilitate the generation of circ1662 based on the intron pairing-driven circularization pattern [98]. Moreover, circRNAs modified by m⁶A can be recognized by readers and exhibit changes in stability, resulting in altered expression [99, 100]. A subset of m⁶A-containing circRNAs may be endoribonucleolyticly degraded by the RNase P/MRP complex, which depends on the cooperative binding of HRSP12 and YTHDF2 [101]. The dynamic balance or the imbalance of circRNA expression is a consequence of the combined effect of these regulatory factors.

m⁶A modulates the distribution of circRNAs

Some studies have demonstrated that the m⁶A modification on circRNAs may modulate their nuclear exportation [60, 102]. This process may depend on the recognition and mediation of m⁶A readers [60]. Despite these initial findings, the mechanisms underlying the subcellular trafficking of m⁶A-circRNAs remains largely unknown.

m⁶A modulates the function of circRNAs

As described above, although considered to be non-coding RNAs, some circRNAs have the potential to encode proteins. Due to their unique structure, the translation of m⁶A modified circRNAs also differs from that of the linear RNAs. In this process, m⁶A-circRNAs are identified by the reader, YTHDF3, which recruits the translation initiation factors, eIF4G2 and eIF3A, to initiate translation in a cap-independent manner [87]. The m⁶A modification also influences the function of circRNAs in the regulation of innate immunity. Unmodified foreign circRNAs can directly trigger RIG-I signaling to promote immune activation; however, m⁶A-circRNAs may recruit YTHDF2 to form a complex with RIG-I and suppress the RIG-I immune signaling [103].

circRNAs modulates m⁶A

Conversely, circRNAs can also regulate m⁶A modification. Some circRNAs can regulate m⁶A by affecting the expression of the m⁶A writers, erasers, and readers [104‐107]. Other circRNAs may influence the functions of m⁶A writers, erasers, and readers [108‐110]. For example, circRNAs can competitively bind to writers and contend modifications, thereby hindering the modification of other RNAs by writers [108]. In addition, circRNAs can not only recruit ALKBH5 to ablate the m⁶A modification of target mRNA, but also capture ALKBH5 to suppress its translocation into the nucleus and impede its role of ablating m⁶A [109, 110]. Generally, circRNAs can only mediately modulate m6A modification by regulating m6A writers, erasers or readers instead of directly affect m6A modification by themselves.

Conclusions and prospectives

m⁶A modification and circRNA biology are undoubtedly current research hotspots, and the crosstalk between the two has attracted increasing attention from the researchers. In this review, we describe the complexity of m⁶A modification and circRNA biology, and present the identified crosstalk between them. Although some efforts have been devoted in this field, the study of correlation between m⁶A and circRNAs remains in the initial stages. In consideration of the current research realities, lots of questions remain to be addressed. In reference to the crosstalk mentioned in the previous section, we will present some perspectives which may represent potential future hot topics. These perspectives are also displayed in Fig. 3.

First, previous studies have only reported that m⁶A in the reverse complementary sequences of flanking introns facilitates the generation of circRNA through the intron pairing-driven circularization pattern [98]. However, other studies have verified that the m⁶A modification in pre-mRNA may regulate RNA-protein interactions and pre-mRNA processing [42‐44]. This regulatory mode has been investigated in mRNA maturation but not in circRNAs biogenesis. Here, we propose that the m⁶A modification in pre-mRNA may affect the binding of some RBPs and regulate the generation of circRNA via RBP-mediated circularization. Whether m⁶A modification can modulate the lariat-driven circularization of circRNAs is also a topic worth examining.

Second, although it has been confirmed that m⁶A can regulate the stability of circRNAs [99, 100], in consideration of the specific circular structure and degradation pathway of circRNAs, is there any difference between circRNAs and linear RNAs in the mechanism of m⁶A regulating stability? Similarly, does the regulation of m⁶A on circRNAs exportation differ from its regulation on linear RNAs? In addition, studies have revealed that m⁶A may modulate the degradation of circRNAs [101]; however, whether this mode can participate in the normal life process or disease development has not yet been explored.

Third, while m⁶A are important initiators in the translation of circRNAs [88], it is unknown whether they are translation sustainers or terminators. Since m⁶A is able to affect RNA-RBP interactions [47], it may also influence the binding of RBPs to circRNAs. Similarly, the m⁶A modification on lncRNA is important for the binding of miRNAs [66], and there is an excellent probability that the m⁶A modification on circRNAs affects miRNA binding. Due to the recent research focus on miRNA sponging, potential m⁶A-mediated miRNA-circRNA interactions may represent another area of research interest.

Fourth, circRNAs can contend the modification of m⁶A writers [108], which may also apply to erasers and readers. In addition, while CircRNAs can recruit m⁶A erasers to ablate m⁶A modifications, it remains unknown whether they can also recruit m⁶A writers and readers to install and identify the m⁶A modifications.

Acknowledgments

Figures in this manuscript were created with BioRender.com.

Declarations

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Competing interests

The authors declare that they have no conflict of interest.

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Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science. 2018;361:1346–9. https://doi.org/10.1126/science.aau1646.CrossRefPubMedPubMedCentral

Barbieri I, Kouzarides T. Role of RNA modifications in cancer. Nat Rev Cancer. 2020;20:303–22. https://doi.org/10.1038/s41568-020-0253-2.CrossRefPubMed

Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37:270–88. https://doi.org/10.1016/j.ccell.2020.02.004.CrossRefPubMedPubMedCentral

Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer. 2020;19:88. https://doi.org/10.1186/s12943-020-01204-7.CrossRefPubMedPubMedCentral

Wiener D, Schwartz S. The epitranscriptome beyond m(6)A. Nat Rev Genet. 2021;22:119–31. https://doi.org/10.1038/s41576-020-00295-8.CrossRefPubMed

Shulman Z, Stern-Ginossar N. The RNA modification N(6)-methyladenosine as a novel regulator of the immune system. Nat Immunol. 2020;21:501–12. https://doi.org/10.1038/s41590-020-0650-4.CrossRefPubMed

Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91. https://doi.org/10.1038/s41576-019-0158-7.CrossRefPubMed

Goodall GJ, Wickramasinghe VO. RNA in cancer. Nat Rev Cancer. 2021;21:22–36. https://doi.org/10.1038/s41568-020-00306-0.CrossRefPubMed

Lei M, Zheng G, Ning Q, Zheng J, Dong D. Translation and functional roles of circular RNAs in human cancer. Mol Cancer. 2020;19:30. https://doi.org/10.1186/s12943-020-1135-7.CrossRefPubMedPubMedCentral

10.

Das A, Gorospe M, Panda AC. The coding potential of circRNAs. Aging (Albany NY). 2018;10:2228–9. https://doi.org/10.18632/aging.101554.CrossRef

11.

Wang X, Ma R, Shi W, Wu Z, Shi Y. Emerging roles of circular RNAs in systemic lupus erythematosus. Mol Ther Nucleic Acids. 2021;24:212–22. https://doi.org/10.1016/j.omtn.2021.02.028.CrossRefPubMedPubMedCentral

12.

Xiao MS, Ai Y, Wilusz JE. Biogenesis and functions of circular RNAs come into focus. Trends Cell Biol. 2020;30:226–40. https://doi.org/10.1016/j.tcb.2019.12.004.CrossRefPubMedPubMedCentral

13.

Chen LL. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol. 2020;21:475–90. https://doi.org/10.1038/s41580-020-0243-y.CrossRefPubMed

14.

Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 2019;20:608–24. https://doi.org/10.1038/s41580-019-0168-5.CrossRefPubMed

15.

Yang Y, Hsu PJ, Chen YS, Yang YG. Dynamic transcriptomic m(6)A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018;28:616–24. https://doi.org/10.1038/s41422-018-0040-8.CrossRefPubMedPubMedCentral

16.

Vu LP, Cheng Y, Kharas MG. The biology of m(6)A RNA methylation in Normal and malignant hematopoiesis. Cancer Discov. 2019;9:25–33. https://doi.org/10.1158/2159-8290.CD-18-0959.CrossRefPubMed

17.

Shi H, Wei J, He C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019;74:640–50. https://doi.org/10.1016/j.molcel.2019.04.025.CrossRefPubMedPubMedCentral

18.

Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6:74. https://doi.org/10.1038/s41392-020-00450-x.CrossRefPubMedPubMedCentral

19.

Ruszkowska A. METTL16, methyltransferase-like protein 16: current insights into structure and function. Int J Mol Sci. 2021;22:2176. https://doi.org/10.3390/ijms22042176.CrossRefPubMedPubMedCentral

20.

Rong B, Zhang Q, Wan J, Xing S, Dai R, Li Y, et al. Ribosome 18S m(6)A methyltransferase METTL5 promotes translation initiation and breast cancer cell growth. Cell Rep. 2020;33:108544. https://doi.org/10.1016/j.celrep.2020.108544.CrossRefPubMed

21.

van Tran N, Ernst FGM, Hawley BR, Zorbas C, Ulryck N, Hackert P, et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019;47:7719–33. https://doi.org/10.1093/nar/gkz619.CrossRefPubMedPubMedCentral

22.

Pinto R, Vagbo CB, Jakobsson ME, Kim Y, Baltissen MP, O'Donohue MF, et al. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 2020;48:830–46. https://doi.org/10.1093/nar/gkz1147.CrossRefPubMed

23.

Ren W, Lu J, Huang M, Gao L, Li D, Wang GG, et al. Structure and regulation of ZCCHC4 in m(6)A-methylation of 28S rRNA. Nat Commun. 2019;10:5042. https://doi.org/10.1038/s41467-019-12923-x.CrossRefPubMedPubMedCentral

24.

Ruzicka K, Zhang M, Campilho A, Bodi Z, Kashif M, Saleh M, et al. Identification of factors required for m(6)A mRNA methylation in Arabidopsis reveals a role for the conserved E3 ubiquitin ligase HAKAI. New Phytol. 2017;215:157–72. https://doi.org/10.1111/nph.14586.CrossRefPubMedPubMedCentral

25.

Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–89. https://doi.org/10.1038/cr.2014.3.CrossRefPubMedPubMedCentral

26.

Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018;4:10. https://doi.org/10.1038/s41421-018-0019-0.CrossRefPubMedPubMedCentral

27.

Patil DP, Chen CK, Pickering BF, Chow A, Jackson C, Guttman M, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537:369–73. https://doi.org/10.1038/nature19342.CrossRefPubMedPubMedCentral

28.

Wen J, Lv R, Ma H, Shen H, He C, Wang J, et al. Zc3h13 regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell. 2018;69:1028–38.e6. https://doi.org/10.1016/j.molcel.2018.02.015.CrossRefPubMedPubMedCentral

29.

Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388–99. https://doi.org/10.1016/j.cell.2015.05.014.CrossRefPubMedPubMedCentral

30.

Zaccara S, Jaffrey SR. A unified model for the function of YTHDF proteins in regulating m(6)A-modified mRNA. Cell. 2020;181:1582–95.e18. https://doi.org/10.1016/j.cell.2020.05.012.CrossRefPubMedPubMedCentral

31.

Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, et al. The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in Glioblastoma stem cells. Cancer Discov. 2021;11:480–99. https://doi.org/10.1158/2159-8290.CD-20-0331.CrossRefPubMed

32.

Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017;27:315–28. https://doi.org/10.1038/cr.2017.15.CrossRefPubMedPubMedCentral

33.

Xiao W, Adhikari S, Dahal U, Chen YS, Hao YJ, Sun BF, et al. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell. 2016;61:507–19. https://doi.org/10.1016/j.molcel.2016.01.012.CrossRefPubMed

34.

Roundtree IA, Luo GZ, Zhang Z, Wang X, Zhou T, Cui Y, et al. YTHDC1 mediates nuclear export of N(6)-methyladenosine methylated mRNAs. Elife. 2017;6:e31311. https://doi.org/10.7554/eLife.31311.CrossRefPubMedPubMedCentral

35.

Xu W, Li J, He C, Wen J, Ma H, Rong B, et al. METTL3 regulates heterochromatin in mouse embryonic stem cells. Nature. 2021;591:317–21. https://doi.org/10.1038/s41586-021-03210-1.CrossRefPubMed

36.

Liu J, Dou X, Chen C, Chen C, Liu C, Xu MM, et al. N (6)-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science. 2020;367:580–6. https://doi.org/10.1126/science.aay6018.CrossRefPubMedPubMedCentral

37.

Liu J, Gao M, He J, Wu K, Lin S, Jin L, et al. The RNA m(6)A reader YTHDC1 silences retrotransposons and guards ES cell identity. Nature. 2021;591:322–6. https://doi.org/10.1038/s41586-021-03313-9.CrossRefPubMed

38.

Li Y, Xia L, Tan K, Ye X, Zuo Z, Li M, et al. N(6)-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2. Nat Genet. 2020;52:870–7. https://doi.org/10.1038/s41588-020-0677-3.CrossRefPubMed

39.

Hsu PJ, Zhu Y, Ma H, Guo Y, Shi X, Liu Y, et al. Ythdc2 is an N(6)-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017;27:1115–27. https://doi.org/10.1038/cr.2017.99.CrossRefPubMedPubMedCentral

40.

Zhou B, Liu C, Xu L, Yuan Y, Zhao J, Zhao W, et al. N(6) -Methyladenosine reader protein YT521-B homology domain-containing 2 suppresses liver Steatosis by regulation of mRNA stability of Lipogenic genes. Hepatology. 2021;73:91–103. https://doi.org/10.1002/hep.31220.CrossRefPubMed

41.

Wojtas MN, Pandey RR, Mendel M, Homolka D, Sachidanandam R, Pillai RS. Regulation of m(6)A transcripts by the 3′-->5′ RNA helicase YTHDC2 is essential for a successful meiotic program in the mammalian Germline. Mol Cell. 2017;68:374–87.e12. https://doi.org/10.1016/j.molcel.2017.09.021.CrossRefPubMed

42.

Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518:560–4. https://doi.org/10.1038/nature14234.CrossRefPubMedPubMedCentral

43.

Liu N, Zhou KI, Parisien M, Dai Q, Diatchenko L, Pan T. N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res. 2017;45:6051–63. https://doi.org/10.1093/nar/gkx141.CrossRefPubMedPubMedCentral

44.

Zhou KI, Shi H, Lyu R, Wylder AC, Matuszek Z, Pan JN, et al. Regulation of co-transcriptional pre-mRNA splicing by m(6)A through the low-complexity protein hnRNPG. Mol Cell. 2019;76:70–81.e9. https://doi.org/10.1016/j.molcel.2019.07.005.CrossRefPubMedPubMedCentral

45.

Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162:1299–308. https://doi.org/10.1016/j.cell.2015.08.011.CrossRefPubMedPubMedCentral

46.

Wang L, Wen M, Cao X. Nuclear hnRNPA2B1 initiates and amplifies the innate immune response to DNA viruses. Science. 2019;365:eaav0758. https://doi.org/10.1126/science.aav0758.CrossRefPubMed

47.

Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95. https://doi.org/10.1038/s41556-018-0045-z.CrossRefPubMedPubMedCentral

48.

Muller S, Bley N, Busch B, Glass M, Lederer M, Misiak C, et al. The oncofetal RNA-binding protein IGF2BP1 is a druggable, post-transcriptional super-enhancer of E2F-driven gene expression in cancer. Nucleic Acids Res. 2020;48:8576–90. https://doi.org/10.1093/nar/gkaa653.CrossRefPubMedPubMedCentral

49.

Wu Z, Shi Y, Lu M, Song M, Yu Z, Wang J, et al. METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. Nucleic Acids Res. 2020;48:11083–96. https://doi.org/10.1093/nar/gkaa816.CrossRefPubMedPubMedCentral

50.

Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, et al. 5′ UTR m(6)A promotes cap-independent translation. Cell. 2015;163:999–1010. https://doi.org/10.1016/j.cell.2015.10.012.CrossRefPubMedPubMedCentral

51.

Hwang SY, Jung H, Mun S, Lee S, Park K, Baek SC, et al. L1 retrotransposons exploit RNA m(6)A modification as an evolutionary driving force. Nat Commun. 2021;12:880. https://doi.org/10.1038/s41467-021-21197-1.CrossRefPubMedPubMedCentral

52.

Wu R, Li A, Sun B, Sun JG, Zhang J, Zhang T, et al. A novel m(6)A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res. 2019;29:23–41. https://doi.org/10.1038/s41422-018-0113-8.CrossRefPubMed

53.

Baquero-Perez B, Antanaviciute A, Yonchev ID, Carr IM, Wilson SA, Whitehouse A. The Tudor SND1 protein is an m(6)A RNA reader essential for replication of Kaposi's sarcoma-associated herpesvirus. Elife. 2019;8:e47261. https://doi.org/10.7554/eLife.47261.CrossRefPubMedPubMedCentral

54.

Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC, et al. Differential m(6)A, m(6)Am, and m(1)a Demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell. 2018;71:973–85.e5. https://doi.org/10.1016/j.molcel.2018.08.011.CrossRefPubMedPubMedCentral

55.

Yang X, Liu QL, Xu W, Zhang YC, Yang Y, Ju LF, et al. m(6)A promotes R-loop formation to facilitate transcription termination. Cell Res. 2019;29:1035–8. https://doi.org/10.1038/s41422-019-0235-7.CrossRefPubMedPubMedCentral

56.

Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015;519:482–5. https://doi.org/10.1038/nature14281.CrossRefPubMedPubMedCentral

57.

Haussmann IU, Bodi Z, Sanchez-Moran E, Mongan NP, Archer N, Fray RG, et al. m(6)A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature. 2016;540:301–4. https://doi.org/10.1038/nature20577.CrossRefPubMed

58.

Goh YT, Koh CWQ, Sim DY, Roca X, Goh WSS. METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing. Nucleic Acids Res. 2020;48:9250–61. https://doi.org/10.1093/nar/gkaa684.CrossRefPubMedPubMedCentral

59.

Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, et al. The U6 snRNA m(6)A methyltransferase METTL16 regulates SAM Synthetase intron retention. Cell. 2017;169:824–35.e14. https://doi.org/10.1016/j.cell.2017.05.003.CrossRefPubMedPubMedCentral

60.

Chen RX, Chen X, Xia LP, Zhang JX, Pan ZZ, Ma XD, et al. N(6)-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis. Nat Commun. 2019;10:4695. https://doi.org/10.1038/s41467-019-12651-2.CrossRefPubMedPubMedCentral

61.

Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, et al. m(6)A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 2019;18:87. https://doi.org/10.1186/s12943-019-1014-2.CrossRefPubMedPubMedCentral

62.

Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20. https://doi.org/10.1038/nature12730.CrossRefPubMed

63.

Choe J, Lin S, Zhang W, Liu Q, Wang L, Ramirez-Moya J, et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature. 2018;561:556–60. https://doi.org/10.1038/s41586-018-0538-8.CrossRefPubMedPubMedCentral

64.

Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552:126–31. https://doi.org/10.1038/nature24678.CrossRefPubMedPubMedCentral

65.

Yang D, Qiao J, Wang G, Lan Y, Li G, Guo X, et al. N6-Methyladenosine modification of lincRNA 1281 is critically required for mESC differentiation potential. Nucleic Acids Res. 2018;46:3906–20. https://doi.org/10.1093/nar/gky130.CrossRefPubMedPubMedCentral

66.

Zhang X, Xu Y, Qian Z, Zheng W, Wu Q, Chen Y, et al. circRNA_104075 stimulates YAP-dependent tumorigenesis through the regulation of HNF4a and may serve as a diagnostic marker in hepatocellular carcinoma. Cell Death Dis. 2018;9:1091. https://doi.org/10.1038/s41419-018-1132-6.CrossRefPubMedPubMedCentral

67.

Zhou WY, Cai ZR, Liu J, Wang DS, Ju HQ, Xu RH. Circular RNA: metabolism, functions and interactions with proteins. Mol Cancer. 2020;19:172. https://doi.org/10.1186/s12943-020-01286-3.CrossRefPubMedPubMedCentral

68.

Ma S, Kong S, Wang F, Ju S. CircRNAs: biogenesis, functions, and role in drug-resistant Tumours. Mol Cancer. 2020;19:119. https://doi.org/10.1186/s12943-020-01231-4.CrossRefPubMedPubMedCentral

69.

Li J, Sun D, Pu W, Wang J, Peng Y. Circular RNAs in cancer: biogenesis, function, and clinical significance. Trends Cancer. 2020;6:319–36. https://doi.org/10.1016/j.trecan.2020.01.012.CrossRefPubMed

70.

Huang C, Liang D, Tatomer DC, Wilusz JE. A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs. Genes Dev. 2018;32:639–44. https://doi.org/10.1101/gad.314856.118.CrossRefPubMedPubMedCentral

71.

Wang S, Zhang K, Tan S, Xin J, Yuan Q, Xu H, et al. Circular RNAs in body fluids as cancer biomarkers: the new frontier of liquid biopsies. Mol Cancer. 2021;20:13. https://doi.org/10.1186/s12943-020-01298-z.CrossRefPubMedPubMedCentral

72.

Li Y, Zheng Q, Bao C, Li S, Guo W, Zhao J, et al. Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis. Cell Res. 2015;25:981–4. https://doi.org/10.1038/cr.2015.82.CrossRefPubMedPubMedCentral

73.

Yang L, Han B, Zhang Z, Wang S, Bai Y, Zhang Y, et al. Extracellular vesicle-mediated delivery of circular RNA SCMH1 promotes functional recovery in rodent and nonhuman primate ischemic stroke models. Circulation. 2020;142:556–74. https://doi.org/10.1161/CIRCULATIONAHA.120.045765.CrossRefPubMed

74.

Jie M, Wu Y, Gao M, Li X, Liu C, Ouyang Q, et al. CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification. Mol Cancer. 2020;19:56. https://doi.org/10.1186/s12943-020-01160-2.CrossRefPubMedPubMedCentral

75.

Conn VM, Hugouvieux V, Nayak A, Conos SA, Capovilla G, Cildir G, et al. A circRNA from SEPALLATA3 regulates splicing of its cognate mRNA through R-loop formation. Nat Plants. 2017;3:17053. https://doi.org/10.1038/nplants.2017.53.CrossRefPubMed

76.

Thomson DW, Dinger ME. Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 2016;17:272–83. https://doi.org/10.1038/nrg.2016.20.CrossRefPubMed

77.

Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, et al. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8. https://doi.org/10.1038/nature11993.CrossRefPubMed

78.

Jiang MP, Xu WX, Hou JC, Xu Q, Wang DD, Tang JH. The emerging role of the interactions between circular RNAs and RNA-binding proteins in common human cancers. J Cancer. 2021;12:5206–19. https://doi.org/10.7150/jca.58182.CrossRefPubMedPubMedCentral

79.

Zheng S, Zhang X, Odame E, Xu X, Chen Y, Ye J, et al. CircRNA-protein interactions in muscle development and diseases. Int J Mol Sci. 2021;22:3262. https://doi.org/10.3390/ijms22063262.CrossRefPubMedPubMedCentral

80.

Huang A, Zheng H, Wu Z, Chen M, Huang Y. Circular RNA-protein interactions: functions, mechanisms, and identification. Theranostics. 2020;10:3503–17. https://doi.org/10.7150/thno.42174.CrossRefPubMedPubMedCentral

81.

Zang J, Lu D, Xu A. The interaction of circRNAs and RNA binding proteins: an important part of circRNA maintenance and function. J Neurosci Res. 2020;98:87–97. https://doi.org/10.1002/jnr.24356.CrossRefPubMed

82.

Tsitsipatis D, Grammatikakis I, Driscoll RK, Yang X, Abdelmohsen K, Harris SC, et al. AUF1 ligand circPCNX reduces cell proliferation by competing with p21 mRNA to increase p21 production. Nucleic Acids Res. 2021;49:1631–46. https://doi.org/10.1093/nar/gkaa1246.CrossRefPubMedPubMedCentral

83.

Lou J, Hao Y, Lin K, Lyu Y, Chen M, Wang H, et al. Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit Gliomagenesis. Mol Cancer. 2020;19:138. https://doi.org/10.1186/s12943-020-01253-y.CrossRefPubMedPubMedCentral

84.

Yu F, Zhang Y, Wang Z, Gong W, Zhang C. Hsa_circ_0030042 regulates abnormal autophagy and protects atherosclerotic plaque stability by targeting eIF4A3. Theranostics. 2021;11:5404–17. https://doi.org/10.7150/thno.48389.CrossRefPubMedPubMedCentral

85.

Li B, Zhu L, Lu C, Wang C, Wang H, Jin H, et al. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat Commun. 2021;12:295. https://doi.org/10.1038/s41467-020-20527-z.CrossRefPubMedPubMedCentral

86.

Wu P, Mo Y, Peng M, Tang T, Zhong Y, Deng X, et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer. 2020;19:22. https://doi.org/10.1186/s12943-020-1147-3.CrossRefPubMedPubMedCentral

87.

Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 2017;27:626–41. https://doi.org/10.1038/cr.2017.31.CrossRefPubMedPubMedCentral

88.

Liang WC, Wong CW, Liang PP, Shi M, Cao Y, Rao ST, et al. Translation of the circular RNA circbeta-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol. 2019;20:84. https://doi.org/10.1186/s13059-019-1685-4.CrossRefPubMedPubMedCentral

89.

Zhang M, Huang N, Yang X, Luo J, Yan S, Xiao F, et al. A novel protein encoded by the circular form of the SHPRH gene suppresses glioma tumorigenesis. Oncogene. 2018;37:1805–14. https://doi.org/10.1038/s41388-017-0019-9.CrossRefPubMed

90.

Xia X, Li X, Li F, Wu X, Zhang M, Zhou H, et al. A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1. Mol Cancer. 2019;18:131. https://doi.org/10.1186/s12943-019-1056-5.CrossRefPubMedPubMedCentral

91.

Zheng X, Chen L, Zhou Y, Wang Q, Zheng Z, Xu B, et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via hippo-YAP signaling. Mol Cancer. 2019;18:47. https://doi.org/10.1186/s12943-019-1010-6.CrossRefPubMedPubMedCentral

92.

Zhang M, Zhao K, Xu X, Yang Y, Yan S, Wei P, et al. A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun. 2018;9:4475. https://doi.org/10.1038/s41467-018-06862-2.CrossRefPubMedPubMedCentral

93.

Kleaveland B, Shi CY, Stefano J, Bartel DP. A network of noncoding regulatory RNAs acts in the mammalian brain. Cell. 2018;174:350–62.e17. https://doi.org/10.1016/j.cell.2018.05.022.CrossRefPubMedPubMedCentral

94.

Hansen TB, Wiklund ED, Bramsen JB, Villadsen SB, Statham AL, Clark SJ, et al. miRNA-dependent gene silencing involving Ago2-mediated cleavage of a circular antisense RNA. EMBO J. 2011;30:4414–22. https://doi.org/10.1038/emboj.2011.359.CrossRefPubMedPubMedCentral

95.

Fischer JW, Busa VF, Shao Y, Leung AKL. Structure-mediated RNA decay by UPF1 and G3BP1. Mol Cell. 2020;78:70–84.e6. https://doi.org/10.1016/j.molcel.2020.01.021.CrossRefPubMedPubMedCentral

96.

Liu CX, Li X, Nan F, Jiang S, Gao X, Guo SK, et al. Structure and degradation of circular RNAs regulate PKR activation in innate immunity. Cell. 2019;177:865–80.e21. https://doi.org/10.1016/j.cell.2019.03.046.CrossRefPubMed

97.

Li Z, Yang HY, Dai XY, Zhang X, Huang YZ, Shi L, et al. CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression. Int J Biol Sci. 2021;17:1178–90. https://doi.org/10.7150/ijbs.57783.CrossRefPubMedPubMedCentral

98.

Chen C, Yuan W, Zhou Q, Shao B, Guo Y, Wang W, et al. N6-methyladenosine-induced circ1662 promotes metastasis of colorectal cancer by accelerating YAP1 nuclear localization. Theranostics. 2021;11:4298–315. https://doi.org/10.7150/thno.51342.CrossRefPubMedPubMedCentral

99.

Wu P, Fang X, Liu Y, Tang Y, Wang W, Li X, et al. N6-methyladenosine modification of circCUX1 confers radioresistance of hypopharyngeal squamous cell carcinoma through caspase1 pathway. Cell Death Dis. 2021;12:298. https://doi.org/10.1038/s41419-021-03558-2.CrossRefPubMedPubMedCentral

100.

Xu J, Wan Z, Tang M, Lin Z, Jiang S, Ji L, et al. N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating beta-catenin signaling. Mol Cancer. 2020;19:163. https://doi.org/10.1186/s12943-020-01281-8.CrossRefPubMedPubMedCentral

101.

Park OH, Ha H, Lee Y, Boo SH, Kwon DH, Song HK, et al. Endoribonucleolytic cleavage of m(6)A-containing RNAs by RNase P/MRP Complex. Mol Cell. 2019;74:494–507.e8. https://doi.org/10.1016/j.molcel.2019.02.034.CrossRefPubMed

102.

Li X, Tian G, Wu J. Novel circGFRalpha1 promotes self-renewal of female Germline stem cells mediated by m(6)A writer METTL14. Front Cell Dev Biol. 2021;9:640402. https://doi.org/10.3389/fcell.2021.640402.CrossRefPubMedPubMedCentral

103.

Chen YG, Chen R, Ahmad S, Verma R, Kasturi SP, Amaya L, et al. N6-Methyladenosine modification controls circular RNA immunity. Mol Cell. 2019;76:96-109.e9. https://doi.org/10.1016/j.molcel.2019.07.016.CrossRefPubMedPubMedCentral

104.

Mo WL, Deng LJ, Cheng Y, Yu WJ, Yang YH, Gu WD. Circular RNA hsa_circ_0072309 promotes tumorigenesis and invasion by regulating the miR-607/FTO axis in non-small cell lung carcinoma. Aging (Albany NY). 2021;13:11629–45. https://doi.org/10.18632/aging.202856.CrossRef

105.

Chi F, Cao Y, Chen Y. Analysis and validation of circRNA-miRNA network in regulating m(6)A RNA methylation modulators reveals CircMAP2K4/miR-139-5p/YTHDF1 Axis involving the proliferation of hepatocellular carcinoma. Front Oncol. 2021;11:560506. https://doi.org/10.3389/fonc.2021.560506.CrossRefPubMedPubMedCentral

106.

Zhang Z, Zhu H, Hu J. CircRAB11FIP1 promoted autophagy flux of ovarian cancer through DSC1 and miR-129. Cell Death Dis. 2021;12:219. https://doi.org/10.1038/s41419-021-03486-1.CrossRefPubMedPubMedCentral

107.

Jiang X, Xing L, Chen Y, Qin R, Song S, Lu Y, et al. CircMEG3 inhibits telomerase activity by reducing Cbf5 in human liver cancer stem cells. Mol Ther Nucleic Acids. 2021;23:310–23. https://doi.org/10.1016/j.omtn.2020.11.009.CrossRefPubMed

108.

Shen Y, Li C, Zhou L, Huang JA. G protein-coupled oestrogen receptor promotes cell growth of non-small cell lung cancer cells via YAP1/QKI/circNOTCH1/m6A methylated NOTCH1 signalling. J Cell Mol Med. 2021;25:284–96. https://doi.org/10.1111/jcmm.15997.CrossRefPubMed

109.

Liu B, Liu N, Zhu X, Yang L, Ye B, Li H, et al. Circular RNA circZbtb20 maintains ILC3 homeostasis and function via Alkbh5-dependent m(6)A demethylation of Nr4a1 mRNA. Cell Mol Immunol. 2021;18:1412–24. https://doi.org/10.1038/s41423-021-00680-1.CrossRefPubMed

110.

Huang R, Zhang Y, Bai Y, Han B, Ju M, Chen B, et al. N(6)-Methyladenosine modification of fatty acid amide hydrolase messenger RNA in circular RNA STAG1-regulated astrocyte dysfunction and depressive-like behaviors. Biol Psychiatry. 2020;88:392–404. https://doi.org/10.1016/j.biopsych.2020.02.018.CrossRefPubMed

Titel: Crosstalk between N6-methyladenosine modification and circular RNAs: current understanding and future directions
verfasst von: Xin Wang
Rui Ma
Xilin Zhang
Lian Cui
Yangfeng Ding
Weimin Shi
Chunyuan Guo
Yuling Shi
Publikationsdatum: 01.12.2021
Verlag: BioMed Central
Erschienen in: Molecular Cancer / Ausgabe 1/2021
Elektronische ISSN: 1476-4598
DOI: https://doi.org/10.1186/s12943-021-01415-6

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Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Crosstalk between N6-methyladenosine modification and circular RNAs: current understanding and future directions

Abstract

Publisher’s Note

Background

RNA m⁶A modification

Participants of m⁶A modification: writers, erasers, and readers

m⁶A writers

m⁶A erasers

m⁶A readers

Biological functions of m⁶A modification

m⁶A modulates RNA transcription, splicing, and structure

m⁶A modulates RNA subcellular localization

m⁶A modulates RNA stability, translation, and binding capacity

CircRNAs

Biogenesis of circRNAs

Exportation and distribution of circRNAs

Biological functions of circRNAs

Degradation of circRNAs

Crosstalk between m⁶A and circular RNAs

m⁶A modulates the expression of circRNAs

m⁶A modulates the distribution of circRNAs

m⁶A modulates the function of circRNAs

circRNAs modulates m⁶A

Conclusions and prospectives

Acknowledgments

Declarations

Competing interests

Publisher’s Note

Neu im Fachgebiet Onkologie

Erhebliches Risiko für Kehlkopfkrebs bei mäßiger Dysplasie

15% bedauern gewählte Blasenkrebs-Therapie

Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Update Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Publisher’s Note

Background

RNA m6A modification

Participants of m6A modification: writers, erasers, and readers

m6A writers

m6A erasers

m6A readers

Biological functions of m6A modification

m6A modulates RNA transcription, splicing, and structure

m6A modulates RNA subcellular localization

m6A modulates RNA stability, translation, and binding capacity

CircRNAs

Biogenesis of circRNAs

Exportation and distribution of circRNAs

Biological functions of circRNAs

Degradation of circRNAs

Crosstalk between m6A and circular RNAs

m6A modulates the expression of circRNAs

m6A modulates the distribution of circRNAs

m6A modulates the function of circRNAs

circRNAs modulates m6A

Conclusions and prospectives

Acknowledgments

Declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Publisher’s Note

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Erhöhtes Risiko fürs Herz unter Checkpointhemmer-Therapie

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Update Onkologie

RNA m⁶A modification

Participants of m⁶A modification: writers, erasers, and readers

m⁶A writers

m⁶A erasers

m⁶A readers

Biological functions of m⁶A modification

m⁶A modulates RNA transcription, splicing, and structure

m⁶A modulates RNA subcellular localization

m⁶A modulates RNA stability, translation, and binding capacity

Crosstalk between m⁶A and circular RNAs

m⁶A modulates the expression of circRNAs

m⁶A modulates the distribution of circRNAs

m⁶A modulates the function of circRNAs

circRNAs modulates m⁶A