Role of the N6-methyladenosine RNA mark in gene regulation and its implications on development and disease

Abstract

Epigenetics is a field that encompasses chemical modifications of DNA and histone proteins, both of which alter gene expression without changing the underlying nucleotide sequence. DNA methylation and modifications of histone tails have been studied in detail and are now known to be global gene regulatory mechanisms. An analogous post-transcriptional modification is chemical modification of specific nucleotides in RNA. Study of RNA modifications is a nascent field as yet, and the significance of these marks in controlling cell growth and differentiation is just beginning to be appreciated. The addition of a methyl group to adenosine (N-methyl-6-adenosine) or m6A is the most abundant modification in mammalian mRNAs. Though identified four decades ago, interest in this particular modification was set off by the discovery that the obesity gene FTO was an RNA demethylase. Since then, many studies have investigated m6A modification in different species. In this review, we summarize the current literature and hypotheses about the presence and function of this ubiquitous RNA modification in mammals, viruses, yeast and plants in terms of the consensus sequence and the methyltransferase/demethylation machinery identified thus far. We discuss its potential role in regulating molecular and physiological processes in each of these organisms, especially its role in RNA splicing, RNA degradation and development. We also enlist the methodologies developed so far, both locus-specific and transcriptome-wide, to study this modification. Lastly, we discuss whether m6A alterations have consequences on modulating disease aetiology, and speculate about its potential role in cancer.

MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3′-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein

“…N 6 -Methyladenosine (m 6 A) 3 is a common modification of RNA molecules. There are about 7600 mRNA transcripts, and more than 300 non-coding RNAs contain the m 6 A sites in humans (1,2). Although the modification exists widely, the biological importance of m 6 A remains largely unknown (3,4).…”

“…The authors declare that they have no conflicts of interest with the contents of this article. 1 To whom correspondence may be addressed. involved in the different diseases, such as cardiac myofibroblast differentiation, pulmonary arterial hypertension, and microvasculature (21)(22)(23).…”

m6a RNA Methylation: The Implications for Health and Disease

“…Furthermore, the activity of a second demethylase, ALKBH5 has also been established. This resurgence in interest has also been accelerated by overcoming a major obstacle in the detection of m 6 A [28], the development of novel techniques and adaptations of old ones, reviewed by Chandola et al (2014) [29]. These have allowed a greater parity of the occurrence and fluidity of this epigenetic modification [30].…”

“…The activation of TLR signalling also induces several anti-cancer proteins and is considered a target for cancer therapy [101]. Furthermore, modification of RNA bases has been shown to enhance/perturb TLR signalling pathways [100,102], leading to the possibility that RNA modification plays a role in cancer progression [29].…”

RNA-MethylPred: A high-accuracy predictor to identify N6-methyladenosine in RNA

“…The m 6 A modification is involved in diverse life activities, such as embryo development, cell apoptosis, spermatogenesis and the circadian clock. As a reversible and dynamic modification, m 6 A is co-regulated by methyltransferases and demethylases [1][2][3].…”