Above the Epitranscriptome: RNA Modifications and Stem Cell Identity

Abstract

Sequence databases and transcriptome-wide mapping have revealed different reversible and dynamic chemical modifications of the nitrogen bases of RNA molecules. Modifications occur in coding RNAs and noncoding-RNAs post-transcriptionally and they can influence the RNA structure, metabolism, and function. The result is the expansion of the variety of the transcriptome. In fact, depending on the type of modification, RNA molecules enter into a specific program exerting the role of the player or/and the target in biological and pathological processes. Many research groups are exploring the role of RNA modifications (alias epitranscriptome) in cell proliferation, survival, and in more specialized activities. More recently, the role of RNA modifications has been also explored in stem cell biology. Our understanding in this context is still in its infancy. Available evidence addresses the role of RNA modifications in self-renewal, commitment, and differentiation processes of stem cells. In this review, we will focus on five epitranscriptomic marks: N6-methyladenosine, N1-methyladenosine, 5-methylcytosine, Pseudouridine (Ψ) and Adenosine-to-Inosine editing. We will provide insights into the function and the distribution of these chemical modifications in coding RNAs and noncoding-RNAs. Mainly, we will emphasize the role of epitranscriptomic mechanisms in the biology of naïve, primed, embryonic, adult, and cancer stem cells.

Keywords: 5-methylcytosine; N1-methyladenosine; N6-methyladenosine; bioinformatics predictive tools; cancer stem cells; epigenetics; erasers proteins; mitochondrial ribosomal RNA; mitochondrial transfer RNA; naïve and primed stem cells; readers; stem cells self-renewal and differentiation; writers.

Figure 1

The figure illustrates the possible chemical modifications at the different messenger RNA (mRNA) nitrogen bases. The preferential location of each mark within the mRNA sequence and the reader proteins are also shown (see the text for details). N6-methyladenosine: m⁶A; Pseudouridine: Ψ; 5-methylcytosine: m⁵C; 5-hydroxymethylcytidine: hm⁵C; N1-methyladenosine: m¹A.

Figure 2

The figure illustrates the chemical modifications at the Adenosine, Cytosine, and Uridine nitrogen bases. In green are the enzymes catalyzing the reaction of addition of a moiety group (writers). In red are the enzymes catalyzing the reaction of deletion of the modification (erasers). The modification sites are colored in blue. The abbreviations of the modified nucleosides are shown in parentheses.