N6-Methyladenosine

Last updated
N6-Methyladenosine
N6-Methyladenosine.svg
Names
IUPAC name
N6-Methyladenosine
Systematic IUPAC name
(2R,3S,4R,5R)-2-(Hydroxymethyl)-5-[6-(methylamino)-9H-purin-9-yl]oxolane-2,3-diol
Other names
m6A
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
UNII
  • InChI=1S/C11H15N5O4/c1-12-9-6-10(14-3-13-9)16(4-15-6)11-8(19)7(18)5(2-17)20-11/h3-5,7-8,11,17-19H,2H2,1H3,(H,12,13,14)/t5-,7-,8-,11-/m1/s1
    Key: VQAYFKKCNSOZKM-IOSLPCCCSA-N
  • n2c1c(ncnc1NC)n(c2)[C@@H]3O[C@@H]([C@@H](O)[C@H]3O)CO
Properties
C11H15N5O4
Molar mass 281.272 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

N6-Methyladenosine (m6A) was originally identified and partially characterised in the 1970s, [1] [2] [3] [4] and is an abundant modification in mRNA and DNA. [5] It is found within some viruses, [4] [3] [6] [7] and most eukaryotes including mammals, [2] [1] [8] [9] insects, [10] plants [11] [12] [13] and yeast. [14] [15] It is also found in tRNA, rRNA, and small nuclear RNA (snRNA) as well as several long non-coding RNA, such as Xist . [16] [17]

Contents

The methylation of adenosine is directed by a large m6A methyltransferase complex containing METTL3, which is the subunit that binds S-adenosyl-L-methionine (SAM). [18] In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU [19] and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA [20] and in bovine prolactin mRNA. [21] More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including METTL14, [22] [23] Wilms tumor 1 associated protein (WTAP), [22] [24] VIRMA [25] and METTL5. [26] Following a 2010 speculation of m6A in mRNA being dynamic and reversible, [27] the discovery of the first m6A demethylase, fat mass and obesity-associated protein (FTO) in 2011 [28] confirmed this hypothesis and revitalized the interests in the study of m6A. A second m6A demethylase alkB homolog 5 (ALKBH5) was later discovered as well. [29]

The biological functions of m6A are mediated through a group of RNA binding proteins that specifically recognize the methylated adenosine on RNA. These binding proteins are named m6A readers. The YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3 and YTHDC1) have been characterized as direct m6A readers and have a conserved m6A-binding pocket. [17] [30] [31] [32] [33] Insulin-like growth factor-2 mRNA-binding proteins 1, 2, and 3 (IGF2BP1–3) are reported as a novel class of m6A readers. [34] IGF2BPs use K homology (KH) domains to selectively recognize m6A-containing RNAs and promote their translation and stability. [34] These m6A readers, together with m6A methyltransferases (writers) and demethylases (erasers), establish a complex mechanism of m6A regulation in which writers and erasers determine the distributions of m6A on RNA, whereas readers mediate m6A-dependent functions. m6A has also been shown to mediate a structural switch termed m6A switch. [35]

The specificity of m6A installation on mRNA is controlled by exon architecture and exon junction complexes. Exon junction complexes suppress m6A methylation near exon-exon junctions by packaging nearby RNA and protecting it from methylation by the m6A methyltransferase complex. m6A regions in long internal and terminal exons, away from exon-exon junctions and exon junction complexes, escape suppression and can be methylated by the methyltransferase complex. [36]

Species distribution

Yeast

In budding yeast (Saccharomyces cerevisiae), the expression of the homologue of METTL3, IME4, is induced in diploid cells in response to nitrogen and fermentable carbon source starvation and is required for mRNA methylation and the initiation of correct meiosis and sporulation. [14] [15] mRNAs of IME1 and IME2, key early regulators of meiosis, are known to be targets for methylation, as are transcripts of IME4 itself. [15]

Plants

In plants, the majority of the m6A is found within 150 nucleotides before the start of the poly(A) tail. [37]

Mutations of MTA, the Arabidopsis thaliana homologue of METTL3, results in embryo arrest at the globular stage. A >90% reduction of m6A levels in mature plants leads to dramatically altered growth patterns and floral homeotic abnormalities. [37]

Mammals

Mapping of m6A in human and mouse RNA has identified over 18,000 m6A sites in the transcripts of more than 7,000 human genes with a consensus sequence of [G/A/U][G>A]m6AC[U>A/C] [16] [17] [38] consistent with the previously identified motif. The localization of individual m6A sites in many mRNAs is highly similar between human and mouse, [16] [17] and transcriptome-wide analysis reveals that m6A is found in regions of high evolutionary conservation. [16] m6A is found within long internal exons and is preferentially enriched within 3' UTRs and around stop codons. m6A within 3' UTRs is also associated with the presence of microRNA binding sites; roughly 2/3 of the mRNAs which contain an m6A site within their 3' UTR also have at least one microRNA binding site. [16] By integrating all m6A sequencing data, a novel database called RMBase has identified and provided ~200,000 sites in the human and mouse genomes corresponding to N6-Methyladenosines (m6A) in RNA. [38]

Precise m6A mapping by m6A-CLIP/IP [39] (briefly m6A-CLIP) revealed that a majority of m6A locates in the last exon of mRNAs in multiple tissues/cultured cells of mouse and human, [39] and the m6A enrichment around stop codons is a coincidence that many stop codons locate round the start of last exons where m6A is truly enriched. [39] The major presence of m6A in last exon (>=70%) allows the potential for 3'UTR regulation, including alternative polyadenylation. [39] The study combining m6A-CLIP with rigorous cell fractionation biochemistry reveals that m6A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. [40] [41]

m6A is susceptible to dynamic regulation both throughout development and in response to cellular stimuli. Analysis of m6A in mouse brain RNA reveals that m6A levels are low during embryonic development and increase dramatically by adulthood. [16] In mESCs and during mouse development, FTO has been shown to mediated LINE1 RNA m6A demethylation and consequently affect local chromatin state and nearby gene transcription. [42] Additionally, silencing the m6A methyltransferase significantly affects gene expression and alternative RNA splicing patterns, resulting in modulation of the p53 (also known as TP53) signalling pathway and apoptosis. [17]

m6A is also found on the RNA components of R-loops in human cells, where it is involved in regulation of stability of RNA:DNA hybrids. [43]

The importance of m6A methylation for physiological processes was recently demonstrated. Inhibition of m6A methylation via pharmacological inhibition of cellular methylations or more specifically by siRNA-mediated silencing of the m6A methylase Mettl3 led to the elongation of the circadian period. In contrast, overexpression of Mettl3 led to a shorter period. The mammalian circadian clock, composed of a transcription feedback loop tightly regulated to oscillate with a period of about 24 hours, is therefore extremely sensitive to perturbations in m6A-dependent RNA processing, likely due to the presence of m6A sites within clock gene transcripts. [44] [45] The effects of global methylation inhibition on the circadian period in mouse cells can be prevented by ectopic expression of an enzyme from the bacterial methyl metabolism. Mouse cells expressing this bacterial protein were resistant to pharmacological inhibition of methyl metabolism, showing no decrease in mRNA m6A methylation or protein methylation. [46]

Clinical significance

Considering the versatile functions of m6A in various physiological processes, it is thus not surprising to find links between m6A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m6A. The linkages between m6A and numerous cancer types have been indicated in reports that include stomach cancer, prostate cancer, breast cancer, pancreatic cancer, kidney cancer, mesothelioma, sarcoma, and leukaemia. [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] The impacts of m6A on cancer cell proliferation might be much more profound with more data emerging. The depletion of METTL3 is known to cause apoptosis of cancer cells and reduce invasiveness of cancer cells, [59] [60] while the activation of ALKBH5 by hypoxia was shown to cause cancer stem cell enrichment. [61] m6A has also been indicated in the regulation of energy homeostasis and obesity, as FTO is a key regulatory gene for energy metabolism and obesity. SNPs of FTO have been shown to associate with body mass index in human populations and occurrence of obesity and diabetes. [62] [63] [64] [65] [66] The influence of FTO on pre-adipocyte differentiation has been suggested. [67] [68] [69] The connection between m6A and neuronal disorders has also been studied. For instance, neurodegenerative diseases may be affected by m6A as the cognate dopamine signalling was shown to be dependent on FTO and correct m6A methylation on key signalling transcripts. [70] The mutations in HNRNPA2B1, a potential reader of m6A, have been known to cause neurodegeneration. [71] The IGF2BP1–3, a novel class of m6A reader, has oncogenic functions. IGF2BP1–3 knockdown or knockout decreased MYC protein expression, cell proliferation and colony formation in human cancer cell lines. [34] The ZC3H13, a member of the m6A methyltransferase complex, markedly inhibited colorectal cancer cells growth when knocked down. [72]

Additionally, m6A has been reported to impact viral infections. Many RNA viruses including SV40, adenovirus, herpes virus, Rous sarcoma virus, and influenza virus have been known to contain internal m6A methylation on virus genomic RNA. [73] Several more recent studies have revealed that m6A regulators govern the efficiency of infection, replication, translation and transport of RNA viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and Zika virus (ZIKV). [74] [75] [76] [77] [78] [79] These results suggest m6A and its cognate factors play crucial roles in regulating virus life cycles and host-viral interactions.

Aside from affecting viruses themselves, m6A modifications can also disrupt the innate immune response. For example, in HBV, m6A modifications were shown to disrupt the recognition of viruses by RIG-1, a pattern recognition receptor in the immune system. Modifications can also disrupt downstream signaling pathways via mechanisms including ubiquitination and changes in the levels of protein expression. [79]

In bacteria

M6A methylation is also widespread in bacteria, influencing functions such as DNA replication, repair, and gene expression, and prokaryotic defense.

In replication, M6A modifications mark DNA regions where the initiation stage takes place as well as regulates precise timing via the Dam methyltransferase in E. coli. [80] [81] Another enzyme, Dam DNA methylase regulates mismatch repair using M6A modifications which influence other repair proteins by recognizing specific mismatches. [82]

In some cases of DNA protection, M6A methylations (along with M4C modifications) play a role in the protection of bacterial DNA by influencing certain endonucleases via the restriction-modification system, decreasing the influence of bacteriophages. One such role is introducing a methyltransferase which recognizes the same target site that restriction enzymes (Type 1 restriction enzymes) attack and modifying it in order to stop such enzymes from attacking bacteria DNA. [83] [84]

In Development

m6A modifications, along with other epigenetic changes, have been shown to play important roles during eukaryotic development. Hematopoietic Stem Cells (HSCs), Neuronal Stem Cells (NSCs) and Primordial Germ Cells (PCGs) have all been shown to undergo m6A modifications during growth and differentiation. Depending on the stage of development, modifications to HSCs can either promote or inhibit stem cell differentiation by affecting the epithelial-to-hemopoietic transition via METTL3 inhibition or depletion. m6A modifications to NSCs can causes changes in brain size, neuron formation, long-term memory, and learning ability. These changes are often caused by inhibition of either METTL or YTHDF readers and writers. In the reproductive system, m6A modifications have been shown to disrupt the maternal-to-zygotic mRNA transition and negatively affect both gamete formation and fertility. Similar to NSCs, inhibition of the METTL and YTHDF families of proteins is often a catalyst for these changes. [85]

Related Research Articles

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.

Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and biology.

<span class="mw-page-title-main">DNA methyltransferase</span> Class of enzymes

In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

<span class="mw-page-title-main">DNA methylation</span> Biological process

DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.

<span class="mw-page-title-main">RNA editing</span> Molecular process

RNA editing is a molecular process through which some cells can make discrete changes to specific nucleotide sequences within an RNA molecule after it has been generated by RNA polymerase. It occurs in all living organisms and is one of the most evolutionarily conserved properties of RNAs. RNA editing may include the insertion, deletion, and base substitution of nucleotides within the RNA molecule. RNA editing is relatively rare, with common forms of RNA processing not usually considered as editing. It can affect the activity, localization as well as stability of RNAs, and has been linked with human diseases.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

AlkB (Alkylation B) is a protein found in E. coli, induced during an adaptive response and involved in the direct reversal of alkylation damage. AlkB specifically removes alkylation damage to single stranded (SS) DNA caused by SN2 type of chemical agents. It efficiently removes methyl groups from 1-methyl adenines, 3-methyl cytosines in SS DNA. AlkB is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. It oxidatively demethylates the DNA substrate. Demethylation by AlkB is accompanied with release of CO2, succinate, and formaldehyde.

<span class="mw-page-title-main">FTO gene</span> Protein-coding gene in the species Homo sapiens

Fat mass and obesity-associated protein also known as alpha-ketoglutarate-dependent dioxygenase FTO is an enzyme that in humans is encoded by the FTO gene located on chromosome 16. As one homolog in the AlkB family proteins, it is the first mRNA demethylase that has been identified. Certain alleles of the FTO gene appear to be correlated with obesity in humans.

<span class="mw-page-title-main">DNA (cytosine-5)-methyltransferase 3A</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene.

<span class="mw-page-title-main">RBM15</span> Protein-coding gene in the species Homo sapiens

Putative RNA-binding protein 15 is a protein that in humans is encoded by the RBM15 gene. It is an RNA-binding protein that acts as a key regulator of N6-Methyladenosine (m6A) methylation of RNAs

<span class="mw-page-title-main">METTL3</span> Gene encoding part of N6-adenosine-methyltransferase

N6-adenosine-methyltransferase 70 kDa subunit (METTL3) is an enzyme that in humans is encoded by the METTL3 gene. METTL3 is located on the human chromosome 14q11.2 and out of the METTL protein family, it is the most studied.

<span class="mw-page-title-main">HBx</span>

HBx is a hepatitis B viral protein. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. It interacts with DDB1 redirecting the ubiquitin ligase activity of the CUL4-DDB1 E3 complexes, which are intimately involved in the intracellular regulation of DNA replication and repair, transcription and signal transduction.

High-throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP) is a variant of CLIP for genome-wide mapping protein–RNA binding sites or RNA modification sites in vivo. HITS-CLIP was originally used to generate genome-wide protein-RNA interaction maps for the neuron-specific RNA-binding protein and splicing factor NOVA1 and NOVA2; since then a number of other splicing factor maps have been generated, including those for PTB, RbFox2, SFRS1, hnRNP C, and even N6-Methyladenosine (m6A) mRNA modifications.

<span class="mw-page-title-main">Cancer epigenetics</span> Field of study in cancer research

Cancer epigenetics is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in a cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in the promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins. There are several medications which have epigenetic impact, that are now used in a number of these diseases.

In molecular biology, the protein domain YTH refers to a member of the YTH family that has been shown to selectively remove transcripts of meiosis-specific genes expressed in mitotic cells.They also play a role in the epitranscriptome as reader proteins for m6A.

Within the field of molecular biology, the epitranscriptome includes all the biochemical modifications of the RNA within a cell. In analogy to epigenetics that describes "functionally relevant changes to the genome that do not involve a change in the nucleotide sequence", epitranscriptomics involves all functionally relevant changes to the transcriptome that do not involve a change in the ribonucleotide sequence. Thus, the epitranscriptome can be defined as the ensemble of such functionally relevant changes.

<span class="mw-page-title-main">Chuan He</span> Chinese-American chemical biologist

Chuan He is a Chinese-American chemical biologist. He currently serves as the John T. Wilson Distinguished Service Professor at the University of Chicago, and an Investigator of the Howard Hughes Medical Institute. He is best known for his work in discovering and deciphering reversible RNA methylation in post-transcriptional gene expression regulation. He was awarded the 2023 Wolf Prize in Chemistry for his work in discovering and deciphering reversible RNA methylation in post-transcriptional gene expression regulation in addition to his contributions to the invention of TAB-seq, a biochemical method that can map 5-hydroxymethylcytosine (5hmC) at base-resolution genome-wide, as well as hmC-Seal, a method that covalently labels 5hmC for its detection and profiling.

<span class="mw-page-title-main">Epitranscriptomic sequencing</span>

In epitranscriptomic sequencing, most methods focus on either (1) enrichment and purification of the modified RNA molecules before running on the RNA sequencer, or (2) improving or modifying bioinformatics analysis pipelines to call the modification peaks. Most methods have been adapted and optimized for mRNA molecules, except for modified bisulfite sequencing for profiling 5-methylcytidine which was optimized for tRNAs and rRNAs.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

The viral epitranscriptome includes all modifications to viral transcripts, studied by viral epitranscriptomics. Like the more general epitranscriptome, these modifications do not affect the sequence of the transcript, but rather have consequences on subsequent structures and functions.

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