LncRNAs and Chromatin Modifications Pattern m⁶A Methylation at the Untranslated Regions of mRNAs

Abstract

New roles for RNA in mediating gene expression are being discovered at an alarming rate. A broad array of pathways control patterning of N⁶-methyladenosine (m⁶A) methylation on RNA transcripts. This review comprehensively discusses long non-coding RNAs (lncRNAs) as an additional dynamic regulator of m⁶A methylation, with a focus on the untranslated regions (UTRs) of mRNAs. Although there is extensive literature describing m⁶A modification of lncRNA, the function of lncRNA in guiding m⁶A writers has not been thoroughly explored. The independent control of lncRNA expression, its heterogeneous roles in RNA metabolism, and its interactions with epigenetic machinery, alludes to their potential in dynamic patterning of m⁶A methylation. While epigenetic regulation by histone modification of H3K36me3 has been demonstrated to pattern RNA m⁶A methylation, these modifications were specific to the coding and 3′UTR regions. However, there are observations that 5′UTR m⁶A is distinct from that of the coding and 3′UTR regions, and substantial evidence supports the active regulation of 5′UTR m⁶A methylation. Consequently, two potential mechanisms in patterning the UTRs m⁶A methylation are discussed; (1) Anti-sense lncRNA (AS-lncRNA) can either bind directly to the UTR, or (2) act indirectly via recruitment of chromatin-modifying complexes to pattern m⁶A. Both pathways can guide the m⁶A writer complex, facilitate m⁶A methylation and modulate protein translation. Findings in the lncRNA-histone-m⁶A axis could potentially contribute to the discovery of new functions of lncRNAs and clarify lncRNA-m⁶A findings in translational medicine.

Introduction

RNA modifications and RNA-RNA interactions are some of the oldest biological building blocks of the cell (Schwartz, 1998; Higgs and Lehman, 2015). Long non-coding RNAs (lncRNAs) are an abundant type of non-protein-coding RNA that have diverse functions in the nucleus, including DNA organization, recruitment of histone proteins, RNA metabolism, and translational control via direct epigenetic interactions (Schmitz et al., 2016). LncRNAs have been described to guide DNA methylation, histone modifications, and, recently, RNA methylation (Kim et al., 2015; Marchese et al., 2017; Chen et al., 2020). While patterned by multiple mechanisms, n⁶-methyladenosine (m⁶A) methylation of RNA is the most abundant internal post-transcriptional modification and is most prevalent on the coding sequence (CDS) and 3′ untranslated region (UTR) (Meyer et al., 2012). The reversible modification of m⁶A methylation is catalyzed by “writer” proteins (Mettl3/Mettl14/WTAP) (Figure 1A), and demethylated by “erasers” (FTO/ALKBH5). M⁶A methylation has been described to be involved in alternative splicing, transport, stability of RNAs and to regulate RNA translation (B. Wu et al., 2017a; Shi H. et al., 2019). Cap-independent translation is a potent ribosome recruitment mechanism that bypasses translational control checkpoints during a rapid cellular response to environmental or physiological insults (Leppek et al., 2018). While present in low abundance, m⁶A methylation at the 5′UTR has been shown to selectively initiate cap-independent protein translation (Meyer et al., 2015; Zhou et al., 2015; Coots et al., 2017). Yet, the mechanisms that govern m⁶A patterning on the 5′UTR are poorly understood.

FIGURE 1

The 5′UTR is a critical regulator of the final product of gene expression given it can either enhance or repress the translational state of messenger RNAs (mRNAs) (Sendoel et al., 2017; Leppek et al., 2018). Since translational control is highly regulated (Silvera et al., 2010; Buffington et al., 2014), and single mRNA transcripts can persistently generate protein products (English et al., 2016), a mechanism that can tag RNAs to bypass canonical translational control is of tremendous significance. As observed in the study of the heat shock response (Meyer et al., 2015; Zhou et al., 2015), changes in m⁶A methylated 5′UTR (m⁶A 5′UTR) can alter a cell’s biological state in response to environmental cues or perturbation (Figure 1). This prompts a significant need to understand 5′UTR m⁶A patterning mechanisms. However, most studies observe a scarcity of m⁶A methylation at the 5′UTR (Fu et al., 2014). Because 5‘UTR methylation is both WTAP-independent (Schwartz et al., 2014) and Zc3h13-independent (Wen et al., 2018), this suggests that it is regulated by other sources (Meyer et al., 2012; Dominissini et al., 2013; Schwartz et al., 2014; Koranda et al., 2018). Recently, knock-out of the Mettl14/Mettl3 associated complex component Vir-like m⁶A methyltransferase associated or VIRMA (a.k.a. KIAA1429), was shown to increase the amount of 5’UTR m⁶A. This suggests that the process may be regulated by protein participants of the Mettl14/Mettl3 complex (Yue et al., 2018). Furthermore, VIRMA upregulation has been associated with tumorigenesis and seminoma cancer, consistent with aberrant gene expression profiles (Lobo et al., 2019). Studies have demonstrated that m⁶A at the 5′UTR can be altered due to biological signals such as normal development (Xiao et al., 2019), neurogenesis (Yoon et al., 2017), HIV infection (Lichinchi et al., 2016), memory formation (Widagdo et al., 2016) and stress response (J. Yu F. et al., 2018), supporting dynamic regulation of m⁶A 5′UTR. However, the mechanism by which transcript- and methylation-site specificity at the 5′UTR is controlled remains elusive (Zhao et al., 2018).

Multiple forms of regulating m⁶A methylation have been described and are frequently being discovered (Huang et al., 2020). For example, the histone modification H3K36me3 (Huang et al., 2019) was found to guide m⁶A methylation co-transcriptionally, and microRNAs (miRNAs) (Chen et al., 2015) were found to mediate binding of Mettl3 to target sites on mRNAs. Yet, both mechanisms are preferential towards m⁶A patterning of the CDS and 3′UTR. Interestingly, there are in-depth descriptions of lncRNAs that recruit chromatin modifiers, and that guide DNA methylation (Savell et al., 2016; F. Yu J. et al., 2018; Mishra and Kanduri, 2019). Non-Coding RNAs are broadly known to act as guides for RNA modifications and m⁶A is no exception; lncRNAs are now accepted as regulators of post-transcriptional modifications (Leighton and Bredy, 2018; Chen et al., 2020). Here, lncRNAs are reviewed as guides for m⁶A UTR patterning and two potential non-mutually exclusive mechanisms by which lncRNAs can dynamically control m⁶A at the UTR are discussed. In one scenario (Figure 1B), lncRNAs bind directly to the UTR of the mRNA transcripts to regulate VIRMA binding and control UTR m⁶A levels, such as lncRNA GATA3-AS (Lan et al., 2019). In the second scenario (Figure 1C), lncRNA regulate epigenetic modifications of histone subunits that ultimately pattern m⁶A on mRNA (Huang et al., 2019). This review provides an in-depth analysis of these two non-opposing mechanisms that may guide m⁶A to the 3′UTR and potentially the 5′UTR, while highlighting the cross-talk between the epigenome and the epitranscriptome.

Co-Transcriptional Nature of m⁶A Methylation, IncRNAs and Histone Modifications

Histone modifiers, m⁶A writers, as well as hundreds of lncRNAs are thought to localize to the same subcellular nuclear compartment. However, whether these biological processes localize and can function simultaneously at a single active gene during transcription, e.g., co-transcriptionally, is a fundamental question in understanding the precise control of m⁶A methylation patterning (Perales and Bentley, 2009; Huang et al., 2020).

M⁶A Methylation

The co-transcriptional nature of m⁶A deposition on RNA molecules was described early in the re-invigoration of the m⁶A modification field (Shi X. et al., 2019). M⁶A writers interact with transcription factors, like FoxO6 (Zong et al., 2020), with transcriptional machinery, like Poll2, along with nascent transcribed RNA (Zhou et al., 2019). Furthermore, the writer Mettl3 can bind directly with both promoter regions (Barbieri et al., 2017) and transcription start sites (TSS) (Xiao et al., 2019), and even with epigenetic machinery like histone methyltransferases (Xu et al., 2021). For example, during TGF-β pathway activation, the transcription factors SMAD2/3 promotes writer complex Mettl3, Mettl14 and WTAP activity to selectively methylate transcripts associated with cell fate specification (Bertero et al., 2018). Additionally, RNA binding proteins that bind to m⁶A sites, e.g. m⁶A “readers,” such as YTHDC1, can also interact with epigenetic machinery (Li et al., 2020). Pivotal findings have been made so far uncovering the co-transcriptional landscape of m⁶A methylation, however, these are likely only the first of many interactions with transcriptional machinery to be discovered. Overall, it is still unclear what patterning mechanisms prime the gene/transcript at the epigenetic level.

LncRNAs in the Nucleus

LncRNAs have long been observed to interact with genomic machinery within the nucleus. These lncRNAs have been described to have direct interactions with DNA enhancer regions [e.g. Pvt1 lncRNA to MYC enhancer (Olivero et al., 2020)], transcription factors (Z. Wang et al., 2018a) (e.g., EPIC1), histones, pre-mRNA, and RNA-binding proteins within the nucleus (Yao et al., 2019). Over 120,000 species of lncRNA have been described to date (Volders et al., 2015), with thousands of lncRNAs identified within the nucleus (Frankish et al., 2019) using sequencing and fluorescent in situ hybridization (Cabili et al., 2015) (FISH). Specific lncRNAs demonstrate subcellular localization at nuclear speckles (Quinodoz et al., 2021), paraspeckles (Bond and Fox, 2009), and other nuclear regions such as nuclear bodies (Chujo and Hirose, 2017). Nuclear localization studies highlight how speckle-associated genomic domains tend to be rich in open-reading frames (ORFs) and highly transcriptionally active (van Steensel and Furlong, 2019). Importantly, nuclear speckles is where m⁶A methylation has been described to occur (Jia et al., 2011; Schöller et al., 2018), and where Mettl14 is known to localize via direct interaction with laminin-A (Zhang M. et al., 2020). While this evidence suggests nuclear speckle localizing lncRNAs could play a regulatory role in m⁶A methylation patterning, more studies are necessary to elucidate the function of lncRNAs within specific compartments of the nucleus.

Histone Modifications and Co-Transcription

In the complex 3D environment of the nucleus, epigenetic machinery regulates gene transcription and repression. The histone proteins H2A, H2B, H3, and H4 are fundamental constituents of the nucleosome, which are modified on their N-terminal tails with reversible chromatin modifications. The best studied modifications occur on H3 and H4, which include histone acetylation (H3K27ac) and various forms of lysine methylation (H3K4me1, H3K27me3 and H3K36me3) (Zhao et al., 2021). Proteins that read these histone modifications can activate or repress DNA accessibility and bind with RNA transcription machinery (Zhao et al., 2021). Conversely, histone proteins respond to signals generated during transcription and pre-mRNA processing. The pre-mRNA processing mechanisms known to interact with histone modifications and transcription machinery include: splicing, RNA editing, 5′ end capping, and, most recently, m⁶A methylation (Bentley, 2002; Huang et al., 2020; Kan et al., 2022). Given the novelty, only a few studies have identified epigenetic-epitranscriptomic network interactions. As described in the following sections, H3K36me3 and H3K27me3 were found to bind with m⁶A writers, suggesting this new branch in the field of RNA modifications is likely to continue to expand (Huang et al., 2019; Wu et al., 2020).

Context Dependent Changes in lncRNA Expression, 5′UTR m⁶A Patterning, and Histone Modifications

Many biological processes dynamically modulate lncRNA expression, m⁶A patterning, and the chromatin landscape (see Table 1). This review presents many of the typical physiological and pathological cell states in which all three of these epigenetic-epitranscriptomic mechanisms exhibit dynamic expression patterns. While this section lists correlational observations, many of the examples delineated here have already been described to exhibit bidirectional regulatory relationships that involve lncRNAs, histone modifications and/or m⁶A methylation.

Changes in 5′UTR m⁶A Patterning

The dynamic mechanisms that govern the precise control of m⁶A methylation is of particular interest in the growing field of RNA modifications (Shi H. et al., 2019). Given that patterns in m⁶A can change rapidly, it has been proposed that 5′UTR m⁶A methylation may be a means of coordinated rapid response to environmental perturbation (Zhou et al., 2015). Differential and often rapid m⁶A methylation of specific transcripts has been described in multiple biological systems such as cancer, development, stress, learning and memory, infection, and cellular reprogramming (See Table 1).

The complexity of the nervous system has generated great interest in the epitranscriptome. A pioneering study of m⁶A in the brain observed dynamic changes in m⁶A levels during cortical neurogenesis and was found to be critical in mediating RNA decay during neuronal maturation (Yoon et al., 2017). In another study, the m⁶A levels at the 5′UTR of the synaptic protein DSCR1.4 increased with BDNF stimulation resulting in axon growth, confirming m⁶A involvement in central nervous system plasticity (Seo et al., 2019) and axon regeneration (Weng et al., 2018a). Interestingly, a slight increase in 5′UTR m⁶A-modified transcripts was observed within synaptosome fractions when compared to whole cell lysate (Merkurjev et al., 2018). Among the noteworthy synaptic RNAs identified by Merkurjev et al. were CaMKIIa and Shank1, that have been previously suggested to undergo non-canonical Cap-independent protein translation (Pinkstaff et al., 2001; Studtmann et al., 2014). The mammalian stress response represents another potent example of a physiological process that exhibits dynamic changes in the epitranscriptome. During stress response, changes in readers (YTHDC1), writers (Mettl3), erasers (FTO) as well as global changes in m⁶A patterns are observed. Specifically, 5′UTR m⁶A increased with response to fasting (Zhou et al., 2018), and exhibited brain region-specific dynamics in stress regulation in rodents (Engel et al., 2018). These studies fortify the notion that 5′ UTR m⁶A methylation acts as a rapid-response mechanism to physiological and environmental change.

Understanding m⁶A methylation patterns during epithelial mesenchymal transition (EMT) of oncogenes is a rapidly expanding field (Yue et al., 2019; Bera and Lewis, 2020). Increases in 5′UTR m⁶A were observed during EMT of cancer cells and during metastasis (Lin et al., 2019). The cross-talk of histone methylation and m⁶A methylation was described in great mechanistic detail and is suggested to be important during pathogen infection and the host immune response (Wu et al., 2020), as well as in playing a significant role in maintaining the pluripotency of stem cells (Huang et al., 2019). However, generally low levels of m⁶A methylation are observed during early phases of development and throughout pluripotency (Aguilo et al., 2015), but this phenomenon is poorly understood. Nevertheless, these lines of evidence support that 5′UTR m⁶A methylation exhibits context dependent patterning and coordinated rapid response.

Dynamic lncRNA Expression

LncRNAs are well described to exhibit differential and cell-type specific expression patterns across multiple biological systems and during cell state changes including cancer (Terashima et al., 2017), stress (Carrieri et al., 2012), development (Pillay et al., 2021) and memory formation (Wang et al., 2017a) (see Table 1).

Production of anti-sense (AS) RNAs is abundant in the human brain (Mills et al., 2016). For instance, AS RNAs are integral to the epigenetic regulation of the activity dependent neuronal cFos gene during memory formation. The anti-sense FOS (AS-Fos) RNA was found to be temporally co-expressed in an activity-dependent manner with cFos mRNA. Upon cFos open reading frame activation, a transcript produced from the 3′UTR, AS-fos RNA, binds to the CpG promoter region of the Fos gene, inhibiting DNA methylation and promoting gene transcription (Savell et al., 2016). Savell et al. found AS-Fos to be essential for long-term memory formation but not short-term memory in the hippocampus during fear learning. This study alludes to the importance of temporarily precise transcriptional control by lncRNAs in the context of memory formation (Savell et al., 2016).

LncRNAs have commonly been studied in the context of stroke. One report found about 80 lncRNAs were differentially expressed during ischemic stroke, including the upregulation of the antisense lncRNA-N1LR(Z. Wu et al., 2017b). LncRNA upregulation is associated with stroke risk and recurrence (Bao et al., 2018), including antisense noncoding RNA in the INK4 locus (ANRILs) (Zhang et al., 2012). Interestingly, the expression of ANRILs is also associated with inflammation and oxidative stress (Cai and Jiang, 2020), as well as melanoma and neural tumors (Pasmant et al., 2007). This suggests lncRNA ANRILs respond to multiple cellular stressors.

Deep-sequencing studies of tumor biopsies and cancer cell lines have identified hundreds and occasionally thousands of differentially expressed lncRNAs. Among these studies, lncRNA EPIC1 (epigenetically-induced lncRNA1) was identified. EPIC1 directly interacts with the oncogene MYC and enhances MYC binding to target gene promoters resulting cell-cycle progression (Wang Y. et al., 2018). The lncRNA MEG3 is differentially expressed in during EMT transition and in multiple forms of cancer (Du et al., 2013; Terashima et al., 2017). MEG3 was found to associate with JARED2, to recruit PRC2, and induce histone H3K27 methylation on the regulatory regions of CDH1 gene. In summary, lncRNAs exhibit dynamic roles in cancer progression, many of which entail direct interactions with genes and histone modifying enzymes.

Alterations in Histone Modifications

Epigenetic machinery is an essential core regulator and stabilizer of gene expression programs during both normal physiological and pathological states. The biological processes that regulate changes in histone modifications are heavily reviewed (Zhao et al., 2021). The epigenetic landscape is generally thought to include DNA methylation, nucleosome remodeling, 3D DNA organization, and reversible histone modifications. This review focuses on the nature of histone modifications and their potential m⁶A pattering capabilities during changes in cellular physiology.

There are hundreds of examples that describe the dynamic regulation and necessity of precise epigenetic control of chromatin remodeling during brain plasticity, stress response and development (see Table 1) (Mossink et al., 2021). Histone modifications such as H3K27ac have been extensively studied in the context of learning and memory formation (Campbell and Wood, 2019). Additionally, histone deacetylase 2 (HDAC2) is activated by glucocorticoid stress hormone and essential in regulating physiological stress response (Wang S. E. et al., 2017). Histone methyltransferases, like KMT2A and KMT2B, that regulate H3K4me are required for working memory and long-term memory formation to occur (Kerimoglu et al., 2013; Jakovcevski et al., 2015). Furthermore, increases in H3K9me2 were observed to exacerbate the anxiolytic response to withdrawal from cocaine addiction (Anderson et al., 2018). These examples highlight the capability of histone modifying enzymes to respond relatively quickly to changes in physiological state, a necessary characteristic for timely regulation of m⁶A patterning.

This review only briefly examines many types of changes in cell state that depend on the epitranscriptome and epigenome for down-stream physiological processes to occur. Importantly, for many of these, lncRNAs play essential roles. Next, many relevant mechanisms by which lncRNA act co-transcriptionally and during RNA pre-processing are discussed, as to further highlight the potential of lncRNA to pattern m⁶A methylation via multiple mechanisms.

Guide Nc-RNAs in RNA Modification and Targeted AS-lncRNA Binding

Non-Coding RNAs are some of the oldest biological building blocks of the cell. This section reviews ncRNAs and lncRNAs interacting directly with RNA transcripts and as guides in RNA modification. Furthermore, given the regulatory implications of m⁶A at the 5′UTR, instances of lncRNAs binding to the untranslated regions of mRNAs are discussed. Additionally, functional categorizations of lncRNAs in terms of biogenesis and mode of action are reviewed. This section serves to contrast lncRNAs that bind with histone modifying enzymes and focuses of lncRNAs binding directly with RNA transcripts.

NcRNAs Act as Guides in RNA Modifications

Non-coding RNAs (ncRNAs) have been studied in great depth for their ability to act as guides in RNA methylation, acetylation and pseudouridylation. These ncRNAs serve as case studies in the analysis of lncRNA-guided m⁶A methylation in the complex nuclear environment. Small nucleolar RNAs (snoRNAs) are abundant ancient ncRNAs that range between 80 and 1,000 nucleotides in length. There are at least 200 guide snoRNAs in humans, necessary for multiple post-transcriptional modifications in eukaryotic rRNAs and tRNAs(Dieci et al., 2009). SnoRNAs guide the methylation (Kiss-Laszlo, 1998; van Nues et al., 2011), acetylation (Sharma et al., 2017), and pseudouridylation (Kiss et al., 2004) of ncRNAs in order to generate functional and mature RNA species. Another example are small Cajal-body-associated RNAs (scaRNAs) that guide the post-transcriptional modification of spliceosomal small nuclear RNA (snRNAs). ScaRNA have been found to bind directly via RNA:RNA interactions with snRNA to guide 2’-O’methylation and pseudouridylation of the transcript (Darzacq et al., 2002). This line of evidence supports nc-RNAs and lncRNAs interacting with target RNAs in complex nuclear environments (Engreitz et al., 2016), acting on multiple RNA metabolism pathways to facilitate post-transcriptional events. However, ncRNAs binding specifically to the 5′ UTR of mRNA transcripts is significant, given the effect on translational control.

LncRNAs can Target the UTRs

LncRNAs are well known to bind directly with target RNA transcripts causing alternative splicing, scaffolding to RNA binding proteins and change in protein translation dynamics (Yao et al., 2019). While less than 10% of developmentally active As-lncRNAs exhibit complimentary sequence overlap with 3′ UTR or 5′ UTRs of protein coding mRNA transcripts (Pillay et al., 2021), there are multiple examples of AS-ncRNAs binding to 5′UTRs. This section highlights examples of lncRNAs binding specifically to 5′UTRs.

The discovery of the antisense lncRNA for ubiquitin carboxyterminal hydrolase L1 (AS-Uchl1) was significant, given it was the first description of a lncRNA regulating protein translation at the ribosomal level (Carrieri et al., 2012). AS-Uchl1 is nuclear enriched, and upon binding with the 5′UTR of UCHL1 mRNA, both are exported to the cytoplasm. AS-Uchl1 then recruit ribosomes to initiate the translation of UCHL1 protein. Given AS-Uchl1 expression was found to be regulated by stress signaling in neurons, this alludes to fast-acting lncRNAs that can alter gene regulatory networks in response to physiological change in state (Carrieri et al., 2012).

Few studies have deciphered the mechanisms of lncRNA and 5′UTR binding. For instance, the ZEB2-AS1 was reported to bind to the 5′UTR of Zeb2 pre-mRNA after EMT. Upon binding, ZEB2-AS1 acts on the spliceosome, facilitating the retention of an internal ribosome entry site (IRES) containing intron in Zeb2 mRNA. The IRES promotes cap-independent protein translation of Zeb2 and down regulates E-cadherin (Beltran et al., 2008). Others have implicated expression of ZEB2-AS1 with shorter overall survival in patients with acute myeloid leukemia (Shi X. et al., 2019). Overall, the description of ZEB2-AS1 is a clear example of lncRNA binding to 5‘UTRs during mRNA co-transcriptional events.

These examples specifically highlight and support how antisense lncRNAs can function in different locations of the cell. AS-Uchl1 is trafficked to the cytoplasm and is an example of lncRNAs functioning outside the nucleus. In contrast, ZEB2-AS1 was an example of a lncRNA that acts within the area it was transcribed. Next, the nomenclature and functional implications of lncRNAs acting near or distant from the site of its transcription is reviewed.

Cis- and Trans-Acting lncRNAs

The specificity of lncRNAs targeting individual mRNAs (or DNA/Chromatin) depends in part on its transcriptional origin within the genome. This review utilizes a broad classification of lncRNAs dependent on their origin and site of action; Cis-acting lncRNAs that act near the site of transcription (Figure 2A), and Trans-acting lncRNAs that act at distant sites from their locus of transcription (Figure 2B), for example, in the cytoplasm (Marchese et al., 2017; Kopp and Mendell, 2018). This classification of lncRNA facilitates interpreting the mechanism by which lncRNAs might guide m⁶A patterning, given the co-transcriptional nature of m⁶A methylation and known nuclear functions in RNA binding of distinct lncRNAs.

FIGURE 2

Cis-acting lncRNAs, or cis-antisense lncRNAs, are well known to function in gene regulation. These can be generated in a variety of ways, including bi-directional transcription during R-Loop formation (Tan-Wong et al., 2019) or presence of bi-directional promoters (Uesaka et al., 2014) (Figure 2A). These local lncRNAs are quite stable and exhibit long half-lives, with an average of 4.8 h, many exceeding 12 h, though of less duration than the mRNAs they regulate (Tani et al., 2015). Most studies agree that AS-lncRNAs mostly localize, and likely function, near their transcriptional loci. Some estimates suggest around 93% of nuclear lncRNAs are Cis-acting lncRNAs (Quinodoz et al., 2021). Given the anti-sense nature of cis-acting AS-lncRNAs, the long half-life, and the immediate proximity to target mRNAs, these AS-lncRNAs make suitable candidates as direct binding partners with the UTR and guides of m⁶A writer machinery. This hypothesis is supported by the observation that GATA3-AS lncRNA binds with GATA3 mRNA to regulate m⁶A patterning (Lan et al., 2019).

Trans-acting lncRNAs, in contrast to cis-acting lncRNAs, function at distant nuclear or cytoplasmic sites from their transcriptional loci of origin (Figure 2B). Common examples of trans-acting lncRNAs might be transcribed from pseudogenes (Muro and Andrade-Navarro, 2010; Johnsson et al., 2013) and large intergenic non-coding RNAs (lincRNAs) (Guttman et al., 2011). Trans-acting lncRNAs are known to interact with epigenetic machinery (Zhao et al., 2010), and it is this involvement in chromatin remodeling that is likely to contribute to a trans-acting pathway that alters UTR methylation patterns. This proposal is enticing, given that trans-acting lncRNAs can affect multiple gene/mRNA species through “multi-way contract” with histone remodeling complexes. This classification of lncRNAs provides insight into how different, sometimes parallel pathways might converge on RNA expression mechanisms.

LncRNAs, Chromatin Remodeling and m⁶A Methylation Suggests Epigenetic Cross-Talk

Examples of lncRNAs in m⁶A Dynamics

Since the first observation that lncRNAs undergo m⁶A methylation (Meyer et al., 2012), a multitude of studies have expanded the repertoire and importance of m⁶A modified lncRNAs(Fazi and Fatica, 2019; Lv et al., 2020; Xue et al., 2020). Conversely, a few yet pivotal studies have identified role of lncRNAs in guiding the m⁶A writer complex, readers, and erasers to mRNA targets (Figure 3A). A particular example is that of the cis-acting lncRNA GATA3-AS and its ability to recruit VIRMA and facilitate the m⁶A modification of the 3′UTR of GATA3 pre-mRNA. The downstream effect of GATA3 m⁶A methylation was disrupted binding of HuR protein, down regulation of GATA3, and increased metastasis of liver cancer (Lan et al., 2019). More studies are necessary to elucidate the mechanism by which lncRNA recruits VIRMA and the structural changes induced by lncRNA-mRNA binding that would alter writer complex activity to pattern m⁶A.

FIGURE 3

M⁶A readers and erasers have been described to utilize both cis- and trans-acting lncRNAs as guides. LINC00857 was observed to cooperate with reader YTHDC1 to increase the stability of SLC7A5 mRNA in colorectal cancer cells (Tang et al., 2021). The lncRNA KB 1980E6.3 was found to form an RNA: protein complex with the m⁶A reader IGF2BP1 to facilitate the recognition and mRNA stability of m⁶A modified c-Myc in breast cancer stem cells (Zhu et al., 2021). LncRNAs have been found to interact with both m⁶A FTO and ALKBH5 Eraser proteins. FOXM1-AS increases the interaction of FOXM1 and ALKBH5, promoting demethylation of FOXM1 decreasing both FOXM1 expression and tumor growth (Zhang et al., 2017). In a similar study, the lncRNA GAS-AS1 was found to promote the ALKBH5-dependent demethylation of GAS mRNA and inhibit cervical cancer proliferation (Wang et al., 2019; Chen et al., 2020). Additionally, the lincRNA CASC15 is thought to recruit the demethylase FTO to SIM2, decreasing SIM2 mRNA stability and promoting esophageal cancer progression (Qin et al., 2020). Furthermore, specific lncRNAs such as CACNA1G-AS1 and ACAP2-IT1 have been predicted to regulate m⁶A readers and writers expression (Zheng et al., 2021). These initial studies provide substantial evidence that lncRNAs have dynamic interactions with m⁶A proteins, and additional research is likely to provide further examples.

Chromatin Modifications and m⁶A Deposition

There is a growing body of literature that describes bi-directional interactions between the epigenome and the epitranscriptome (Figure 3A). This was first observed in the context of m⁶A methylation upon knock-down of m⁶A writer Mettl14, which altered the expression of histone modifying proteins (Y. Wang Z. et al., 2018). Since then, manipulations of readers, writers, and erasers, as well as the m⁶A modification itself, have been found to impact histone modifications. See Kan et al. for recent review (Kan et al., 2022). A clear example was the observation that m⁶A could co-transcriptionally direct the demethylation of histone H3K9me2 (Li et al., 2020). This occurs by m⁶A reader YTHDC1 physically interacting with the H3K9me2 demethylase KDM3B at m⁶A-associated chromatin regions, promoting H3K9me2 demethylation and increasing overall gene expression. In another example, H3K27me3 was described as a barrier for m⁶A modification during transcription. Furthermore, the histone demethylase KDM6B that targets H3K27me3 directly recruits writers Mettl3 and Mettl14 to facilitate m⁶A methylation of co-transcribing mRNAs while simultaneously promoting transcription (Wu et al., 2020).

Recently, chromatin remodeling by H3K36me3 was observed to pattern m⁶A at the CDS and 3′UTR regions of RNA (Huang et al., 2019). Specifically, H3K36me3 scantly effected m⁶A levels in the 5′UTR in contrast to the CDS and 3′UTR. Furthermore, the repressive histone mark H3K9me3 was negatively correlated with m⁶A peaks, and metagene profiles of m⁶A at H3K36me3-negative sites correlated with increased 5′UTR methylation (Huang et al., 2019). Additionally, all the members of the core m⁶A writer complex, Mettl14, Mettl3 and WTAP, were found to bind with H3K36me3 and not with H3K9me3. However, members of the associated writer complex, VIRMA, Zc3h13, and Hakai were not tested. Interestingly, individual shRNA silencing of Mettl14, Mettl3 or WTAP did not dissociate the remaining m⁶A writer complex proteins from H3K36me3, which warrants future investigation.

As described, H3K36me3 peaks were anti-correlated with m⁶A at the 5′UTR (Huang et al., 2019). This discrepancy H3K36me3 relative to m⁶A patterning can be rationalized by considering the “histone code.” It is generally accepted that a gene is occupied by multiple nucleosomes, given that a nucleosome repeat consists of 140–200 bp of DNA. While the length of the mammalian 5′UTR can range between few nucleotides to several thousand, the median length of the 5′UTR in humans and mice is of 218 and 175, respectively (Leppek et al., 2018). Additionally, the first nucleosome immediately after the transcriptional start site (TSS), e.g., the one that may occupy the 5′UTR, exhibits distinct regulatory dynamics when compared to those of the CDS (Zhang and Pugh, 2011). These correlations warrant further exploration of how the epigenetic landscape patterns m⁶A on the 5′UTRs co-transcriptionally. Consequently, other histone post-translational modifications and the role of 3D DNA organization need to be explored in the context of m⁶A methylation.

LncRNA Interacting With Chromatin Organizers

There is an extensive body of literature that describes lncRNAs interacting with the histone modifiers (Yao et al., 2019) (Figure 3A). Interestingly, lncRNA databases predict that at least 20% of lncRNAs guide DNA/protein and chromatin interactions within the nucleus (Volders et al., 2015). This is impressive, given over 10,000 have been predicted to exist (Volders et al., 2015). This account supports the abundant discovery of lncRNAs that interact with chromatin modifiers. This section reviews major findings of lncRNAs interacting with histone methylation proteins, as to highlight the potential of lncRNAs to interact with histone modifiers, enabling m⁶A patterning of mRNA transcripts.

As previously mentioned, H3K36me3 can guide m⁶A methylation co-transcriptionally (Huang et al., 2019). Multiple lncRNAs such as MEG3 (Terashima et al., 2017), Kcnq1ot1 (Pandey et al., 2008) and Air (Nagano et al., 2008) interact directly with histone methyltransferases for H3K36, and specifically regulate H3K36me3. LncRNAs have been found to interact with a variety of histone methyltransferases. An interesting example is that of HOTTIP, a divergently expressed lncRNA that promotes entire gene-expression programs by H3K4me3 patterning (Wang et al., 2011). In addition, the lncRNA Hotair that binds to G-A base pair rich DNA, correlates with H3K27me3 peaks (Chu et al., 2011). Deep-sequencing has also revealed both cis- and trans-acting lncRNAs, with 218 confirmed lincRNAs that bind directly with the Polycomb repressive complex 2 (PRC2), a protein complex that exhibits histone methyltransferase activity primarily on H3K27me3 (Zhao et al., 2010).

Final Remarks

It is unlikely any specific pathway will be found to exclusively regulate m⁶A methylation patterns. This is perhaps due to the diversity of proteins within the writer complex contributing to a combinatorial mechanism to dictate m⁶A deposition. While lncRNAs may not be the exclusive mechanism that guides UTR m⁶A methylation, it is a contributor of m⁶A patterning in RNA, as it is for DNA and histones. A continuum of interesting phenomena hasbeen described to pattern the RNA modifications, and future research will likely describe these multiple mechanisms as cofactors in the crosstalk of the epigenome and the epitranscriptome (Figure 3B). Such findings will elucidate previously undescribed RNA interactions to which disease or single nucleotide polymorphisms (SNPs) may be attributed. Future research will provide more examples of extensive cross talk between the epigenome and epitranscriptome. Most likely positive and negative feedback systems, as well as sources of illness and targets of intervention.

References

• 1

  AguiloF.ZhangF.SanchoA.FidalgoM.Di CeciliaS.VashishtA.et al (2015). Coordination of M 6 A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming. Cell Stem Cell17 (6), 689–704. 10.1016/j.stem.2015.09.005

  • CrossRef
  • Google Scholar

• 2

  AndersonE. M.LarsonE. B.GuzmanD.WissmanA. M.NeveR. L.NestlerE. J.et al (2018). Overexpression of the Histone Dimethyltransferase G9a in Nucleus Accumbens Shell Increases Cocaine Self-Administration, Stress-Induced Reinstatement, and Anxiety. J. Neurosci.38 (4), 803–813. 10.1523/JNEUROSCI.1657-17.2017

  • CrossRef
  • Google Scholar

• 3

  ApreaJ.CalegariF. (2015). Long Non‐coding RNA S in Corticogenesis: Deciphering the Non‐coding Code of the Brain. Embo J.34 (23), 2865–2884. 10.15252/embj.201592655

  • CrossRef
  • Google Scholar

• 4

  ApreaJ.LescheM.MassaliniS.PrenningerS.AlexopoulouD.DahlA.et al (2015). Identification and Expression Patterns of Novel Long Non-coding RNAs in Neural Progenitors of the Developing Mammalian Cortex. Neurogenesis2 (1), e995524. 10.1080/23262133.2014.995524

  • CrossRef
  • Google Scholar

• 5

  AudasT. E.LeeS. (2016). Stressing Out over Long Noncoding RNA. Biochim. Biophys. Acta (Bba) - Gene Regul. Mech.1859 (1), 184–191. 10.1016/j.bbagrm.2015.06.010

  • CrossRef
  • Google Scholar

• 6

  BaoM.-H.SzetoV.YangB. B.ZhuS.-z.SunH.-S.FengZ.-P. (2018). Long Non-coding RNAs in Ischemic Stroke. Cell Death Dis9 (3), 281. 10.1038/s41419-018-0282-x

  • CrossRef
  • Google Scholar

• 7

  BarbieriI.TzelepisK.PandolfiniL.ShiJ.Millán-ZambranoG.RobsonS. C.et al (2017). Promoter-bound METTL3 Maintains Myeloid Leukaemia by m6A-dependent Translation Control. Nature552 (7683), 126–131. 10.1038/nature24678

  • CrossRef
  • Google Scholar

• 8

  BatistaP. J.MolinieB.WangJ.QuK.ZhangJ.LiL.et al (2014). m6A RNA Modification Controls Cell Fate Transition in Mammalian Embryonic Stem Cells. Cell Stem Cell15 (6), 707–719. 10.1016/j.stem.2014.09.019

  • CrossRef
  • Google Scholar

• 9

  BeltranM.PuigI.PeñaC.GarcíaJ. M.ÁlvarezA. B.PeñaR.et al (2008). A Natural Antisense Transcript Regulates Zeb2/Sip1 Gene Expression during Snail1-Induced Epithelial-Mesenchymal Transition. Genes Dev.22 (6), 756–769. 10.1101/gad.455708

  • CrossRef
  • Google Scholar

• 10

  BentleyD. (2002). The mRNA Assembly Line: Transcription and Processing Machines in the Same Factory. Curr. Opin. Cel Biol.14 (3), 336–342. 10.1016/S0955-0674(02)00333-2

  • CrossRef
  • Google Scholar

• 11

  BeraA.LewisS. M. (2020). Regulation of Epithelial-To-Mesenchymal Transition by Alternative Translation Initiation Mechanisms and its Implications for Cancer Metastasis. Ijms21 (11), 4075. 10.3390/ijms21114075

  • CrossRef
  • Google Scholar

• 12

  BerteroA.BrownS.MadrigalP.OsnatoA.OrtmannD.YiangouL.et al (2018). The SMAD2/3 Interactome Reveals that TGFβ Controls m6A mRNA Methylation in Pluripotency. Nature555 (7695), 256–259. 10.1038/nature25784

  • CrossRef
  • Google Scholar

• 13

  BondC. S.FoxA. H. (2009). Paraspeckles: Nuclear Bodies Built on Long Noncoding RNA. J. Cel Biol.186 (5), 637–644. 10.1083/jcb.200906113

  • CrossRef
  • Google Scholar

• 14

  BuffingtonS. A.HuangW.Costa-MattioliM. (2014). Translational Control in Synaptic Plasticity and Cognitive Dysfunction. Annu. Rev. Neurosci.37 (1), 17–38. 10.1146/annurev-neuro-071013-014100

  • CrossRef
  • Google Scholar

• 15

  CabiliM. N.DunaginM. C.McClanahanP. D.BiaeschA.Padovan-MerharO.RegevA.et al (2015). Localization and Abundance Analysis of Human lncRNAs at Single-Cell and Single-Molecule Resolution. Genome Biol.16 (1), 20. 10.1186/s13059-015-0586-4

  • CrossRef
  • Google Scholar

• 16

  CaiR.JiangJ. (2020). LncRNA ANRIL Silencing Alleviates High Glucose-Induced Inflammation, Oxidative Stress, and Apoptosis via Upregulation of MME in Podocytes. Inflammation43 (6), 2147–2155. 10.1007/s10753-020-01282-1

  • CrossRef
  • Google Scholar

• 17

  CampbellR. R.WoodM. A. (2019). How the Epigenome Integrates Information and Reshapes the Synapse. Nat. Rev. Neurosci.20 (3), 133–147. 10.1038/s41583-019-0121-9

  • CrossRef
  • Google Scholar

• 18

  CarrieriC.CimattiL.BiagioliM.BeugnetA.ZucchelliS.FedeleS.et al (2012). Long Non-coding Antisense RNA Controls Uchl1 Translation through an Embedded SINEB2 Repeat. Nature491 (7424), 454–457. 10.1038/nature11508

  • CrossRef
  • Google Scholar

• 19

  ChenT.HaoY.-J.ZhangY.LiM.-M.WangM.HanW.et al (2015). m6A RNA Methylation Is Regulated by MicroRNAs and Promotes Reprogramming to Pluripotency. Cell Stem Cell16 (3), 289–301. 10.1016/j.stem.2015.01.016

  • CrossRef
  • Google Scholar

• 20

  ChenY.LinY.ShuY.HeJ.GaoW. (2020). Interaction between N6-Methyladenosine (m6A) Modification and Noncoding RNAs in Cancer. Mol. Cancer19 (1), 94. 10.1186/s12943-020-01207-4

  • CrossRef
  • Google Scholar

• 21

  ChuC.QuK.ZhongF. L.ArtandiS. E.ChangH. Y. (2011). Genomic Maps of Long Noncoding RNA Occupancy Reveal Principles of RNA-Chromatin Interactions. Mol. Cel44 (4), 667–678. 10.1016/j.molcel.2011.08.027

  • CrossRef
  • Google Scholar

• 22

  ChujoT.HiroseT. (2017). Nuclear Bodies Built on Architectural Long Noncoding RNAs: Unifying Principles of Their Construction and Function. Mol. Cell40 (12), 889–896. 10.14348/molcells.2017.0263

  • CrossRef
  • Google Scholar

• 23

  CootsR. A.LiuX.-M.MaoY.DongL.ZhouJ.WanJ.et al (2017). m6A Facilitates eIF4F-independent mRNA Translation. Mol. Cel68 (3), 504–514. e7. 10.1016/j.molcel.2017.10.002

  • CrossRef
  • Google Scholar

• 24

  DarzacqX.JádyB. E.VerheggenC.KissA. M.BertrandE.KissT.et al (2002). Cajal Body-specific Small Nuclear RNAs: a Novel Class of 2'-O-Methylation and Pseudouridylation Guide RNAs. EMBO J.21 (11), 2746–2756. 10.1093/emboj/21.11.2746

  • CrossRef
  • Google Scholar

• 25

  DevauxY.ZangrandoJ.SchroenB.CreemersE. E.PedrazziniT.ChangC. P.et al (2015). Long Noncoding RNAs in Cardiac Development and Ageing. Nat. Rev. Cardiol.12 (7), 415–425. 10.1038/nrcardio.2015.55

  • CrossRef
  • Google Scholar

• 26

  DieciG.PretiM.MontaniniB. (2009). Eukaryotic snoRNAs: A Paradigm for Gene Expression Flexibility. Genomics94 (2), 83–88. 10.1016/j.ygeno.2009.05.002

  • CrossRef
  • Google Scholar

• 27

  DominissiniD.Moshitch-MoshkovitzS.Salmon-DivonM.AmariglioN.RechaviG. (2013). Transcriptome-wide Mapping of N6-Methyladenosine by m6A-Seq Based on Immunocapturing and Massively Parallel Sequencing. Nat. Protoc.8 (1), 176–189. 10.1038/nprot.2012.148

  • CrossRef
  • Google Scholar

• 28

  DuZ.FeiT.VerhaakR. G. W.SuZ.ZhangY.BrownM.et al (2013). Integrative Genomic Analyses Reveal Clinically Relevant Long Noncoding RNAs in Human Cancer. Nat. Struct. Mol. Biol.20 (7), 908–913. 10.1038/nsmb.2591

  • CrossRef
  • Google Scholar

• 29

  EngelM.EggertC.KaplickP. M.EderM.RöhS.TietzeL.et al (2018). The Role of m6A/m-RNA Methylation in Stress Response Regulation. Neuron99 (2), 389–403. e9. 10.1016/j.neuron.2018.07.009

  • CrossRef
  • Google Scholar

• 30

  EngreitzJ. M.OllikainenN.GuttmanM. (2016). Long Non-coding RNAs: Spatial Amplifiers that Control Nuclear Structure and Gene Expression. Nat. Rev. Mol. Cel Biol17 (12), 756–770. 10.1038/nrm.2016.126

  • CrossRef
  • Google Scholar

• 31

  FaziF.FaticaA. (2019). Interplay between N6-Methyladenosine (m6A) and Non-coding RNAs in Cell Development and Cancer. Front. Cel Dev. Biol.7 (June), 1–11. 10.3389/fcell.2019.00116

  • CrossRef
  • Google Scholar

• 32

  FrankishA.DiekhansM.FerreiraA.-M.JohnsonR.JungreisI.LovelandJ.et al (2019). GENCODE Reference Annotation for the Human and Mouse Genomes. Nucleic Acids Res.47 (D1), D766–D773. 10.1093/nar/gky955

  • CrossRef
  • Google Scholar

• 33

  FuY.DominissiniD.RechaviG.HeC. (2014). Gene Expression Regulation Mediated through Reversible m6A RNA Methylation. Nat. Rev. Genet.15 (5), 293–306. 10.1038/nrg3724

  • CrossRef
  • Google Scholar

• 34

  GoffL. A.GroffA. F.SauvageauM.Trayes-GibsonZ.Sanchez-GomezD. B.MorseM.et al (2015). Spatiotemporal Expression and Transcriptional Perturbations by Long Noncoding RNAs in the Mouse Brain. Proc. Natl. Acad. Sci. USA112 (22), 6855–6862. 10.1073/pnas.1411263112

  • CrossRef
  • Google Scholar

• 35

  GoldenS. A.ChristoffelD. J.HeshmatiM.HodesG. E.MagidaJ.DavisK.et al (2013). Epigenetic Regulation of RAC1 Induces Synaptic Remodeling in Stress Disorders and Depression. Nat. Med.19 (3), 337–344. 10.1038/nm.3090

  • CrossRef
  • Google Scholar

• 36

  GuttmanM.DonagheyJ.CareyB. W.GarberM.GrenierJ. K.MunsonG.et al (2011). lincRNAs Act in the Circuitry Controlling Pluripotency and Differentiation. Nature477 (7364), 295–300. 10.1038/nature10398

  • CrossRef
  • Google Scholar

• 37

  HiggsP. G.LehmanN. (2015). The RNA World: Molecular Cooperation at the Origins of Life. Nat. Rev. Genet.16 (1), 7–17. 10.1038/nrg3841

  • CrossRef
  • Google Scholar

• 38

  HuangH.WengH.ChenJ. (2020). The Biogenesis and Precise Control of RNA m6A Methylation. Trends Genet.36 (1), 44–52. 10.1016/j.tig.2019.10.011

  • CrossRef
  • Google Scholar

• 39

  HuangH.WengH.ZhouK.WuT.ZhaoB. S.SunM.et al (2019). Histone H3 Trimethylation at Lysine 36 Guides m6A RNA Modification Co-transcriptionally. Nature567 (7748), 414–419. 10.1038/s41586-019-1016-7

  • CrossRef
  • Google Scholar

• 40

  JakovcevskiM.RuanH.ShenE. Y.DincerA.JavidfarB.MaQ.et al (2015). Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory. J. Neurosci.35 (13), 5097–5108. 10.1523/JNEUROSCI.3004-14.2015

  • CrossRef
  • Google Scholar

• 41

  JiaG.FuY.ZhaoX.DaiQ.ZhengG.YangY.et al (2011). N6-Methyladenosine in Nuclear RNA Is a Major Substrate of the Obesity-Associated FTO. Nat. Chem. Biol.7 (12), 885–887. 10.1038/nchembio.687

  • CrossRef
  • Google Scholar

• 42

  JohnssonP.AckleyA.VidarsdottirL.LuiW.-O.CorcoranM.GrandérD.et al (2013). A Pseudogene Long-Noncoding-RNA Network Regulates PTEN Transcription and Translation in Human Cells. Nat. Struct. Mol. Biol.20 (4), 440–446. 10.1038/nsmb.2516

  • CrossRef
  • Google Scholar

• 43

  KanR. L.ChenJ.SallamT. (2022). Crosstalk between Epitranscriptomic and Epigenetic Mechanisms in Gene Regulation. Trends Genet.38 (2), 182–193. 10.1016/j.tig.2021.06.014

  • CrossRef
  • Google Scholar

• 44

  KerimogluC.Agis-BalboaR. C.KranzA.StillingR.Bahari-JavanS.Benito-GaragorriE.et al (2013). Histone-Methyltransferase MLL2 (KMT2B) Is Required for Memory Formation in Mice. J. Neurosci.33 (8), 3452–3464. 10.1523/JNEUROSCI.3356-12.2013

  • CrossRef
  • Google Scholar

• 45

  KimD. H.MarinovG. K.PepkeS.SingerZ. S.HeP.WilliamsB.et al (2015). Single-Cell Transcriptome Analysis Reveals Dynamic Changes in lncRNA Expression during Reprogramming. Cell Stem Cell16 (1), 88–101. 10.1016/j.stem.2014.11.005

  • CrossRef
  • Google Scholar

• 46

  KissA. M.JádyB. E.BertrandE.KissT. (2004). Human Box H/ACA Pseudouridylation Guide RNA Machinery. Mol. Cel Biol24 (13), 5797–5807. 10.1128/MCB.24.13.5797-5807.2004

  • CrossRef
  • Google Scholar

• 47

  Kiss-LaszloZ. (1998). Sequence and Structural Elements of Methylation Guide snoRNAs Essential for Site-specific Ribose Methylation of Pre-rRNA. EMBO J.17 (3), 797–807. 10.1093/emboj/17.3.797

  • CrossRef
  • Google Scholar

• 48

  KoppF.MendellJ. T. (2018). Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell172 (3), 393–407. 10.1016/j.cell.2018.01.011

  • CrossRef
  • Google Scholar

• 49

  KorandaJ. L.DoreL.ShiH.PatelM. J.VaasjoL. O.RaoM. N.et al (2018). Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning. Neuron99 (2), 283–292. 10.1016/j.neuron.2018.06.007

  • CrossRef
  • Google Scholar

• 50

  LanT.LiH.ZhangD.XuL.LiuH.HaoX.et al (2019). KIAA1429 Contributes to Liver Cancer Progression through N6-methyladenosine-dependent post-transcriptional Modification of GATA3. Mol. Cancer18 (1), 186. 10.1186/s12943-019-1106-z

  • CrossRef
  • Google Scholar

• 51

  LeightonL.BredyT. (2018). Functional Interplay between Small Non-coding RNAs and RNA Modification in the Brain. ncRNA4 (2), 15. 10.3390/ncrna4020015

  • CrossRef
  • Google Scholar

• 52

  LeppekK.DasR.BarnaM. (2018). Functional 5′ UTR mRNA Structures in Eukaryotic Translation Regulation and How to Find Them. Nat. Rev. Mol. Cel Biol19 (3), 158–174. 10.1038/nrm.2017.103

  • CrossRef
  • Google Scholar

• 53

  LiY.XiaL.TanK.YeX.ZuoZ.LiM.et al (2020). N6-Methyladenosine Co-transcriptionally Directs the Demethylation of Histone H3K9me2. Nat. Genet.52 (9), 870–877. 10.1038/s41588-020-0677-3

  • CrossRef
  • Google Scholar

• 54

  LiangG.HeJ.ZhangY. (2012). Kdm2b Promotes Induced Pluripotent Stem Cell Generation by Facilitating Gene Activation Early in Reprogramming. Nat. Cel Biol14 (5), 457–466. 10.1038/ncb2483

  • CrossRef
  • Google Scholar

• 55

  LichinchiG.GaoS.SaletoreY.GonzalezG. M.BansalV.WangY.et al (2016). Dynamics of the Human and Viral m6A RNA Methylomes during HIV-1 Infection of T Cells. Nat. Microbiol.1 (4), 16011. 10.1038/nmicrobiol.2016.11

  • CrossRef
  • Google Scholar

• 56

  LinX.ChaiG.WuY.LiJ.ChenF.LiuJ.et al (2019). RNA m6A Methylation Regulates the Epithelial Mesenchymal Transition of Cancer Cells and Translation of Snail. Nat. Commun.10 (1), 2065. 10.1038/s41467-019-09865-9

  • CrossRef
  • Google Scholar

• 57

  LoboJ.CostaA. L.CantanteM.GuimarãesR.LopesP.AntunesL.et al (2019). M6A RNA Modification and its Writer/reader VIRMA/YTHDF3 in Testicular Germ Cell Tumors: A Role in Seminoma Phenotype Maintenance. J. Transl Med.17 (1), 1–13. 10.1186/s12967-019-1837-z

  • CrossRef
  • Google Scholar

• 58

  LvZ.SunL.XuQ.XingC.YuanY. (2020). Joint Analysis of lncRNA m6A Methylome and lncRNA/mRNA Expression Profiles in Gastric Cancer. Cancer Cel Int20 (1), 464. 10.1186/s12935-020-01554-8

  • CrossRef
  • Google Scholar

• 59

  MarazziI.GreenbaumB. D.LowD. H. P.GuccioneE. (2018). Chromatin Dependencies in Cancer and Inflammation. Nat. Rev. Mol. Cel Biol19 (4), 245–261. 10.1038/nrm.2017.113

  • CrossRef
  • Google Scholar

• 60

  MarcheseF. P.RaimondiI.HuarteM. (2017). The Multidimensional Mechanisms of Long Noncoding RNA Function. Genome Biol.18 (1), 1–13. 10.1186/s13059-017-1348-2

  • CrossRef
  • Google Scholar

• 61

  MerkurjevD.HongW.-T.IidaK.OomotoI.GoldieB. J.YamagutiH.et al (2018). Synaptic N6-Methyladenosine (m6A) Epitranscriptome Reveals Functional Partitioning of Localized Transcripts. Nat. Neurosci.21 (July), 1004–1014. 10.1038/s41593-018-0173-6

  • CrossRef
  • Google Scholar

• 62

  MeyerK. D.PatilD. P.ZhouJ.ZinovievA.SkabkinM. A.ElementoO.et al (2015). 5′ UTR m6A Promotes Cap-independent Translation. Cell163 (4), 999–1010. 10.1016/j.cell.2015.10.012

  • CrossRef
  • Google Scholar

• 63

  MeyerK. D.SaletoreY.ZumboP.ElementoO.MasonC. E.JaffreyS. R. (2012). Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and Near Stop Codons. Cell149 (7), 1635–1646. 10.1016/j.cell.2012.05.003

  • CrossRef
  • Google Scholar

• 64

  MillsJ. D.ChenB. J.UeberhamU.ArendtT.JanitzM. (2016). The Antisense Transcriptome and the Human Brain. J. Mol. Neurosci.58 (1), 1–15. 10.1007/s12031-015-0694-3

  • CrossRef
  • Google Scholar

• 65

  MishraK.KanduriC. (2019). Understanding Long Noncoding RNA and Chromatin Interactions: What We Know So Far. ncRNA5 (4), 54. 10.3390/ncrna5040054

  • CrossRef
  • Google Scholar

• 66

  MossinkB.NegwerM.SchubertD.Nadif KasriN. (2021). The Emerging Role of Chromatin Remodelers in Neurodevelopmental Disorders: a Developmental Perspective. Cell. Mol. Life Sci.78 (6), 2517–2563. 10.1007/s00018-020-03714-5

  • CrossRef
  • Google Scholar

• 67

  MuroE. M.Andrade-NavarroM. A. (2010). Pseudogenes as an Alternative Source of Natural Antisense Transcripts. BMC Evol. Biol.10 (1), 338. 10.1186/1471-2148-10-338

  • CrossRef
  • Google Scholar

• 68

  NaganoT.MitchellJ. A.SanzL. A.PaulerF. M.Ferguson-SmithA. C.FeilR.et al (2008). The Air Noncoding RNA Epigenetically Silences Transcription by Targeting G9a to Chromatin. Science322 (5908), 1717–1720. 10.1126/science.1163802

  • CrossRef
  • Google Scholar

• 69

  OliveroC. E.Martínez-TerrobaE.ZimmerJ.LiaoC.TesfayeE.HooshdaranN.et al (2020). p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis. Mol. Cel77 (4), 761–774. e8. 10.1016/j.molcel.2019.12.014

  • CrossRef
  • Google Scholar

• 70

  OnderT. T.KaraN.CherryA.SinhaA. U.ZhuN.BerntK. M.et al (2012). Chromatin-modifying Enzymes as Modulators of Reprogramming. Nature483 (7391), 598–602. 10.1038/nature10953

  • CrossRef
  • Google Scholar

• 71

  PandeyR. R.MondalT.MohammadF.EnrothS.RedrupL.KomorowskiJ.et al (2008). Kcnq1ot1 Antisense Noncoding RNA Mediates Lineage-specific Transcriptional Silencing through Chromatin-Level Regulation. Mol. Cel32 (2), 232–246. 10.1016/j.molcel.2008.08.022

  • CrossRef
  • Google Scholar

• 72

  PasmantE.LaurendeauI.HéronD.VidaudM.VidaudD.BiècheI. (2007). Characterization of a Germ-Line Deletion, Including the Entire INK4/ARF Locus, in a Melanoma-Neural System Tumor Family: Identification of ANRIL, an Antisense Noncoding RNA Whose Expression Coclusters with ARF. Cancer Res.67 (8), 3963–3969. 10.1158/0008-5472.CAN-06-2004

  • CrossRef
  • Google Scholar

• 73

  PeralesR.BentleyD. (2009). "Cotranscriptionality": The Transcription Elongation Complex as a Nexus for Nuclear Transactions. Mol. Cel36 (2), 178–191. 10.1016/j.molcel.2009.09.018

  • CrossRef
  • Google Scholar

• 74

  PillayS.TakahashiH.CarninciP.KanhereA. (2021). Antisense RNAs during Early Vertebrate Development Are Divided in Groups with Distinct Features. Genome Res.31 (6), 995–1010. 10.1101/gr.262964.120

  • CrossRef
  • Google Scholar

• 75

  PinkstaffJ. K.ChappellS. A.MauroV. P.EdelmanG. M.KrushelL. A. (2001). Internal Initiation of Translation of Five Dendritically Localized Neuronal mRNAs. Proc. Natl. Acad. Sci.98 (5), 2770–2775. 10.1073/pnas.051623398

  • CrossRef
  • Google Scholar

• 76

  PirogovS. A.GvozdevV. A.KlenovM. S. (2019). Long Noncoding RNAs and Stress Response in the Nucleolus. Cells8 (7), 668. 10.3390/cells8070668

  • CrossRef
  • Google Scholar

• 77

  QinB.DongM.WangZ.WanJ.XieY.JiaoY.et al (2020). Long Non-coding RNA CASC15 F-acilitates E-sophageal S-quamous C-ell C-arcinoma T-umorigenesis via D-ecreasing SIM2 S-tability via FTO-mediated D-emethylation. Oncol. Rep.45 (3), 1059–1071. 10.3892/or.2020.7917

  • CrossRef
  • Google Scholar

• 78

  QuinodozS. A.JachowiczJ. W.BhatP.OllikainenN.BanerjeeA. K.GoronzyI. N.et al (2021). RNA Promotes the Formation of Spatial Compartments in the Nucleus. Cell184 (23), 5775–5790. e30. 10.1016/j.cell.2021.10.014

  • CrossRef
  • Google Scholar

• 79

  SavellK. E.GallusN. V. N.SimonR. C.BrownJ. A.RevannaJ. S.OsbornM. K.et al (2016). Extra-coding RNAs Regulate Neuronal DNA Methylation Dynamics. Nat. Commun.7 (May). 10.1038/ncomms12091

  • CrossRef
  • Google Scholar

• 80

  SchmitzS. U.GroteP.HerrmannB. G. (2016). Mechanisms of Long Noncoding RNA Function in Development and Disease. Cel. Mol. Life Sci.73 (13), 2491–2509. 10.1007/s00018-016-2174-5

  • CrossRef
  • Google Scholar

• 81

  SchöllerE.WeichmannF.TreiberT.RingleS.TreiberN.FlatleyA.et al (2018). Interactions, Localization, and Phosphorylation of the m6A Generating METTL3-METTL14-WTAP Complex. RNA24 (4), 499–512. 10.1261/rna.064063.117

  • CrossRef
  • Google Scholar

• 82

  SchwartzA. W. (1998). Origins of the RNA World in the Molecular Origins of Life. Nat. Rev. Genet.16, 237–254. 10.1017/CBO9780511626180.013

  • CrossRef
  • Google Scholar

• 83

  SchwartzS.MumbachM. R.JovanovicM.WangT.MaciagK.BushkinG. G.et al (2014). Perturbation of m6A Writers Reveals Two Distinct Classes of mRNA Methylation at Internal and 5′ Sites. Cel Rep.8 (1), 284–296. 10.1016/j.celrep.2014.05.048

  • CrossRef
  • Google Scholar

• 84

  SendoelA.DunnJ. G.RodriguezE. H.NaikS.GomezN. C.HurwitzB.et al (2017). Translation from Unconventional 5′ Start Sites Drives Tumour Initiation. Nature541 (7638), 494–499. 10.1038/nature21036

  • CrossRef
  • Google Scholar

• 85

  SeoJ.-Y.JungY.KimD.-Y.RyuH. G.LeeJ.KimS. W.et al (2019). DAP5 Increases Axonal Outgrowth of Hippocampal Neurons by Enhancing the Cap-independent Translation of DSCR1.4 mRNA. Cel Death Dis10 (2), 49. 10.1038/s41419-018-1299-x

  • CrossRef
  • Google Scholar

• 86

  SharmaS.YangJ.van NuesR.WatzingerP.KötterP.LafontaineD. L. J.et al (2017). Specialized Box C/D snoRNPs Act as Antisense Guides to Target RNA Base Acetylation. Plos Genet.13 (5), e1006804. 10.1371/journal.pgen.1006804

  • CrossRef
  • Google Scholar

• 87

  ShiH.WeiJ.HeC. (2019a). Where, when, and How: Context-dependent Functions of RNA Methylation Writers, Readers, and Erasers. Mol. Cel74 (4), 640–650. 10.1016/j.molcel.2019.04.025

  • CrossRef
  • Google Scholar

• 88

  ShiX.LiJ.MaL.WenL.WangQ.YaoH.et al (2019b). Overexpression of ZEB2-AS1 lncRNA I-s A-ssociated with P-oor C-linical O-utcomes in A-cute M-yeloid L-eukemia. Oncol. Lett.17 (6), 4935–4947. 10.3892/ol.2019.10149

  • CrossRef
  • Google Scholar

• 89

  ShirahamaS.MikiA.KaburakiT.AkimitsuN. (2020). Long Non-coding RNAs Involved in Pathogenic Infection. Front. Genet.11 (May), 3389. 10.3389/fgene.2020.00454

  • CrossRef
  • Google Scholar

• 90

  SilveraD.FormentiS. C.SchneiderR. J. (2010). Translational Control in Cancer. Nat. Rev. Cancer10 (4), 254–266. 10.1038/nrc2824

  • CrossRef
  • Google Scholar

• 91

  SridharanR.Gonzales-CopeM.ChronisC.BonoraG.McKeeR.HuangC.et al (2013). Proteomic and Genomic Approaches Reveal Critical Functions of H3K9 Methylation and Heterochromatin Protein-1γ in Reprogramming to Pluripotency. Nat. Cel Biol15 (7), 872–882. 10.1038/ncb2768

  • CrossRef
  • Google Scholar

• 92

  StudtmannK.Ölschläger-SchüttJ.BuckF.RichterD.SalaC.BockmannJ.et al (2014). A Non-canonical Initiation Site Is Required for Efficient Translation of the Dendritically Localized Shank1 mRNA. PLoS ONE9 (2), e88518. 10.1371/journal.pone.0088518

  • CrossRef
  • Google Scholar

• 93

  SunL.FangJ. (2016). Epigenetic Regulation of Epithelial-Mesenchymal Transition. Cel. Mol. Life Sci.73 (23), 4493–4515. 10.1007/s00018-016-2303-1

  • CrossRef
  • Google Scholar

• 94

  Tan-WongS. M.DhirS.ProudfootN. J. (2019). R-loops Promote Antisense Transcription across the Mammalian Genome. Mol. Cel76 (4), 600–616. e6. 10.1016/j.molcel.2019.10.002

  • CrossRef
  • Google Scholar

• 95

  TangS.LiuQ.XuM. (2021). LINC00857 Promotes Cell Proliferation and Migration in Colorectal Cancer by Interacting with YTHDC1 and Stabilizing SLC7A5. Oncol. Lett.22 (2), 578. 10.3892/ol.2021.12839

  • CrossRef
  • Google Scholar

• 96

  TaniH.ImamachiN.MizutaniR.ImamuraK.KwonY.MiyazakiS.et al (2015). Genome-Wide Analysis of Long Noncoding RNA Turnover. Methods Mol. Biol.1262, 305–320. 10.1007/978-1-4939-2253-6_19

  • CrossRef
  • Google Scholar

• 97

  TerashimaM.TangeS.IshimuraA.SuzukiT. (2017). MEG3 Long Noncoding RNA Contributes to the Epigenetic Regulation of Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines. J. Biol. Chem.292 (1), 82–99. 10.1074/jbc.M116.750950

  • CrossRef
  • Google Scholar

• 98

  UesakaM.NishimuraO.GoY.NakashimaK.AgataK.ImamuraT. (2014). Bidirectional Promoters Are the Major Source of Gene Activation-Associated Non-coding RNAs in Mammals. BMC Genomics15 (1), 35. 10.1186/1471-2164-15-35

  • CrossRef
  • Google Scholar

• 99

  van NuesR. W.GrannemanS.KudlaG.SloanK. E.ChickenM.TollerveyD.et al (2011). Box C/D snoRNP Catalysed Methylation Is Aided by Additional Pre-rRNA Base-Pairing. EMBO J.30 (12), 2420–2430. 10.1038/emboj.2011.148

  • CrossRef
  • Google Scholar

• 100

  van SteenselB.FurlongE. E. M. (2019). The Role of Transcription in Shaping the Spatial Organization of the Genome. Nat. Rev. Mol. Cel Biol20 (6), 327–337. 10.1038/s41580-019-0114-6

  • CrossRef
  • Google Scholar

• 101

  VoldersP.-J.VerheggenK.MenschaertG.VandepoeleK.MartensL.VandesompeleJ.et al (2015). An Update on LNCipedia: a Database for Annotated Human lncRNA Sequences. Nucleic Acids Res.43 (D1), D174–D180. 10.1093/nar/gku1060

  • CrossRef
  • Google Scholar

• 102

  WaltherK.SchulteL. N. (2021). The Role of lncRNAs in Innate Immunity and Inflammation. RNA Biol.18 (5), 587–603. 10.1080/15476286.2020.1845505

  • CrossRef
  • Google Scholar

• 103

  WangA.WangJ.LiuY.ZhouY. (2017a). Mechanisms of Long Non-coding RNAs in the Assembly and Plasticity of Neural Circuitry. Front. Neural Circuits11 (October). 10.3389/fncir.2017.00076

  • CrossRef
  • Google Scholar

• 104

  WangK. C.YangY. W.LiuB.SanyalA.Corces-ZimmermanR.ChenY.et al (2011). A Long Noncoding RNA Maintains Active Chromatin to Coordinate Homeotic Gene Expression. Nature472 (7341), 120–124. 10.1038/nature09819

  • CrossRef
  • Google Scholar

• 105

  WangS. E.KoS. Y.JoS.ChoiM.LeeS. H.JoH.-R.et al (2017b). TRPV1 Regulates Stress Responses through HDAC2. Cel Rep.19 (2), 401–412. 10.1016/j.celrep.2017.03.050

  • CrossRef
  • Google Scholar

• 106

  WangX.ZhangJ.WangY. (2019). Long Noncoding RNA GAS5-AS1 Suppresses Growth and Metastasis of Cervical Cancer by Increasing GAS5 Stability. Am. J. Transl Res.11 (8), 4909–4921.

  • Google Scholar

• 107

  WangY.LiY.YueM.WangJ.KumarS.Wechsler-ReyaR. J.et al (2018b). N6-methyladenosine RNA Modification Regulates Embryonic Neural Stem Cell Self-Renewal through Histone Modifications. Nat. Neurosci.21 (2), 195–206. 10.1038/s41593-017-0057-1

  • CrossRef
  • Google Scholar

• 108

  WangZ.YangB.ZhangM.GuoW.WuZ.WangY.et al (2018a). lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer. Cancer Cell33 (4), 706–e9. e9. 10.1016/j.ccell.2018.03.006

  • CrossRef
  • Google Scholar

• 109

  WenJ.LvR.MaH.ShenH.HeC.WangJ.et al (2018). Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol. Cel69 (6), 1028–1038. e6. 10.1016/j.molcel.2018.02.015

  • CrossRef
  • Google Scholar

• 110

  WengY.-L.WangX.AnR.CassinJ.VissersC.LiuY.et al (2018a). Epitranscriptomic m6A Regulation of Axon Regeneration in the Adult Mammalian Nervous System. Neuron97 (2), 313–325. e6. 10.1016/j.neuron.2017.12.036

  • CrossRef
  • Google Scholar

• 111

  WidagdoJ.ZhaoQ.-Y.KempenM.-J.TanM. C.RatnuV. S.WeiW.et al (2016). Experience-Dependent Accumulation of N 6 -Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice. J. Neurosci.36 (25), 6771–6777. 10.1523/JNEUROSCI.4053-15.2016

  • CrossRef
  • Google Scholar

• 112

  WuB.LiL.HuangY.MaJ.MinJ. (2017a). Readers, Writers and Erasers of N6-Methylated Adenosine Modification. Curr. Opin. Struct. Biol.47, 67–76. 10.1016/j.sbi.2017.05.011

  • CrossRef
  • Google Scholar

• 113

  WuC.ChenW.HeJ.JinS.LiuY.YiY.et al (2020). Interplay of M 6 A and H3K27 Trimethylation Restrains Inflammation during Bacterial Infection. Sci. Adv.6 (34), eaba0647. 10.1126/sciadv.aba0647

  • CrossRef
  • Google Scholar

• 114

  WuP.ZuoX.DengH.LiuX.LiuL.JiA. (2013). Roles of Long Noncoding RNAs in Brain Development, Functional Diversification and Neurodegenerative Diseases. Brain Res. Bull.97, 69–80. 10.1016/j.brainresbull.2013.06.001

  • CrossRef
  • Google Scholar

• 115

  WuZ.WuP.ZuoX.YuN.QinY.XuQ.et al (2017b). LncRNA-N1LR Enhances Neuroprotection against Ischemic Stroke Probably by Inhibiting P53 Phosphorylation. Mol. Neurobiol.54 (10), 7670–7685. 10.1007/s12035-016-0246-z

  • CrossRef
  • Google Scholar

• 116

  XiaoS.CaoS.HuangQ.XiaL.DengM.YangM.et al (2019). The RNA N6-Methyladenosine Modification Landscape of Human Fetal Tissues. Nat. Cel Biol21 (5), 651–661. 10.1038/s41556-019-0315-4

  • CrossRef
  • Google Scholar

• 117

  XuW.LiJ.HeC.WenJ.MaH.RongB.et al (2021). METTL3 Regulates Heterochromatin in Mouse Embryonic Stem Cells. Nature591 (7849), 317–321. 10.1038/s41586-021-03210-1

  • CrossRef
  • Google Scholar

• 118

  XueL.LiJ.LinY.LiuD.YangQ.JianJ.et al (2020). m 6 A Transferase METTL3‐induced lncRNA ABHD11‐AS1 Promotes the Warburg Effect of Non‐small‐cell Lung Cancer. J. Cel Physiol236, 2649–2658. 10.1002/jcp.30023

  • CrossRef
  • Google Scholar

• 119

  YaoR.-W.WangY.ChenL.-L. (2019). Cellular Functions of Long Noncoding RNAs. Nat. Cel Biol21 (5), 542–551. 10.1038/s41556-019-0311-8

  • CrossRef
  • Google Scholar

• 120

  YoonK.-J.RingelingF. R.VissersC.JacobF.PokrassM.Jimenez-CyrusD.et al (2017). Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation. Cell171 (4), 877–889. e17. 10.1016/j.cell.2017.09.003

  • CrossRef
  • Google Scholar

• 121

  YoonY. J.WuB.BuxbaumA. R.DasS.TsaiA.EnglishB. P.et al (2016). Glutamate-induced RNA Localization and Translation in Neurons. Proc. Natl. Acad. Sci. USA113 (44), E6877–E6886. 10.1073/pnas.1614267113

  • CrossRef
  • Google Scholar

• 122

  YuF.ZhangG.ShiA.HuJ.LiF.ZhangX.et al (2018a). LnChrom: A Resource of Experimentally Validated lncRNA-Chromatin Interactions in Human and Mouse. Database2018, 1–7. 10.1093/database/bay039

  • CrossRef
  • Google Scholar

• 123

  YuJ.LiY.WangT.ZhongX. (2018b). Modification of N6-Methyladenosine RNA Methylation on Heat Shock Protein Expression. PLOS ONE13 (6), e0198604. 10.1371/journal.pone.0198604

  • CrossRef
  • Google Scholar

• 124

  YueB.SongC.YangL.CuiR.ChengX.ZhangZ.et al (2019). METTL3-mediated N6-Methyladenosine Modification Is Critical for Epithelial-Mesenchymal Transition and Metastasis of Gastric Cancer. Mol. Cancer18 (1), 1–15. 10.1186/s12943-019-1065-4

  • CrossRef
  • Google Scholar

• 125

  YueY.LiuJ.CuiX.CaoJ.LuoG.ZhangZ.et al (2018). VIRMA Mediates Preferential m6A mRNA Methylation in 3′UTR and Near Stop Codon and Associates with Alternative Polyadenylation. Cell Discov4 (1), 10. 10.1038/s41421-018-0019-0

  • CrossRef
  • Google Scholar

• 126

  ZhangB.ZhengH.HuangB.LiW.XiangY.PengX.et al (2016). Allelic Reprogramming of the Histone Modification H3K4me3 in Early Mammalian Development. Nature537 (7621), 553–557. 10.1038/nature19361

  • CrossRef
  • Google Scholar

• 127

  ZhangJ.AoY.ZhangZ.MoY.PengL.JiangY.et al (2020a). Lamin A Safeguards the M 6 A Methylase METTL14 Nuclear Speckle Reservoir to Prevent Cellular Senescence. Aging Cell19 (10), 1–9. 10.1111/acel.13215

  • CrossRef
  • Google Scholar

• 128

  ZhangM.ZhaiY.ZhangS.DaiX.LiZ. (2020b). Roles of N6-Methyladenosine (m6A) in Stem Cell Fate Decisions and Early Embryonic Development in Mammals. Front. Cel Dev. Biol.8 (August), 1–15. 10.3389/fcell.2020.00782

  • CrossRef
  • Google Scholar

• 129

  ZhangS.ZhaoB. S.ZhouA.LinK.ZhengS.LuZ.et al (2017). m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer Cell31 (4), 591–606. e6. 10.1016/j.ccell.2017.02.013

  • CrossRef
  • Google Scholar

• 130

  ZhangW.ChenY.LiuP.ChenJ.SongL.TangY.et al (2012). Variants on Chromosome 9p21.3 Correlated with ANRIL Expression Contribute to Stroke Risk and Recurrence in a Large Prospective Stroke Population. Stroke43 (1), 14–21. 10.1161/STROKEAHA.111.625442

  • CrossRef
  • Google Scholar

• 131

  ZhangZ.PughB. F. (2011). High-Resolution Genome-wide Mapping of the Primary Structure of Chromatin. Cell144 (2), 175–186. 10.1016/j.cell.2011.01.003

  • CrossRef
  • Google Scholar

• 132

  ZhaoB. S.NachtergaeleS.RoundtreeI. A.HeC. (2018). Our Views of Dynamic N6-Methyladenosine RNA Methylation. Rna24 (3), 268–272. 10.1261/rna.064295.117

  • CrossRef
  • Google Scholar

• 133

  ZhaoJ.OhsumiT. K.KungJ. T.OgawaY.GrauD. J.SarmaK.et al (2010). Genome-wide Identification of Polycomb-Associated RNAs by RIP-Seq. Mol. Cel40 (6), 939–953. 10.1016/j.molcel.2010.12.011

  • CrossRef
  • Google Scholar

• 134

  ZhaoS.AllisC. D.WangG. G. (2021). The Language of Chromatin Modification in Human Cancers. Nat. Rev. Cancer21 (7), 413–430. 10.1038/s41568-021-00357-x

  • CrossRef
  • Google Scholar

• 135

  ZhengH.HuangB.ZhangB.XiangY.DuZ.XuQ.et al (2016). Resetting Epigenetic Memory by Reprogramming of Histone Modifications in Mammals. Mol. Cel63 (6), 1066–1079. 10.1016/j.molcel.2016.08.032

  • CrossRef
  • Google Scholar

• 136

  ZhengJ.GuoJ.CaoB.ZhouY.TongJ. (2021). Identification and Validation of lncRNAs Involved in m6A Regulation for Patients with Ovarian Cancer. Cancer Cel Int21 (1), 363. 10.1186/s12935-021-02076-7

  • CrossRef
  • Google Scholar

• 137

  ZhouJ.WanJ.GaoX.ZhangX.JaffreyS. R.QianS.-B. (2015). Dynamic m6A mRNA Methylation Directs Translational Control of Heat Shock Response. Nature526 (7574), 591–594. 10.1038/nature15377

  • CrossRef
  • Google Scholar

• 138

  ZhouJ.WanJ.ShuX. E.MaoY.LiuX.-M.YuanX.et al (2018). N6-Methyladenosine Guides mRNA Alternative Translation during Integrated Stress Response. Mol. Cel69 (4), 636–647. e7. 10.1016/j.molcel.2018.01.019

  • CrossRef
  • Google Scholar

• 139

  ZhouK. I.ShiH.LyuR.WylderA. C.MatuszekŻ.PanJ. N.et al (2019). Regulation of Co-transcriptional Pre-mRNA Splicing by m6A through the Low-Complexity Protein hnRNPG. Mol. Cel76 (1), 70–81. e9. 10.1016/j.molcel.2019.07.005

  • CrossRef
  • Google Scholar

• 140

  ZhuP.HeF.HouY.TuG.LiQ.JinT.et al (2021). A Novel Hypoxic Long Noncoding RNA KB-1980E6.3 Maintains Breast Cancer Stem Cell Stemness via Interacting with IGF2BP1 to Facilitate C-Myc mRNA Stability. Oncogene40 (9), 1609–1627. 10.1038/s41388-020-01638-9

  • CrossRef
  • Google Scholar

• 141

  ZongX.WangH.XiaoX.ZhangY.HuY.WangF.et al (2020). Enterotoxigenic Escherichia coli Infection Promotes Enteric Defensin Expression via FOXO6-METTL3-m6A-Gpr161 Signalling axis. RNA Biol.18 (00), 576–586. 10.1080/15476286.2020.1820193

  • CrossRef
  • Google Scholar