Modulation of Bacterial sRNAs Activity by Epigenetic Modifications: Inputs from the Eukaryotic miRNAs

Abstract

Trans-encoded bacterial regulatory RNAs (sRNAs) are functional analogues of eukaryotic microRNAs (miRNAs). These RNA classes act by base-pairing complementarity with their RNA targets to modulate gene expression (transcription, half-life and/or translation). Based on base-pairing, algorithms predict binding and the impact of small RNAs on targeted-RNAs expression and fate. However, other actors are involved such as RNA binding proteins and epigenetic modifications of the targeted and small RNAs. Post-transcriptional base modifications are widespread in all living organisms where they lower undesired RNA folds through conformation adjustments and influence RNA pairing and stability, especially if remodeling their ends. In bacteria, sRNAs possess RNA modifications either internally (methylation, pseudouridinylation) or at their ends. Nicotinamide adenine dinucleotide were detected at 5'-ends, and polyadenylation can occur at 3'-ends. Eukaryotic miRNAs possess N⁶-methyladenosine (m⁶A), A editing into I, and non-templated addition of uridines at their 3'-ends. Biological functions and enzymes involved in those sRNA and micro RNA epigenetic modifications, when known, are presented and challenged.

Keywords: RNA modifications; bacterial regulatory RNAs; biogenesis; editing; epigenetics; methylation; miRNAs; trans-acting RNA.

Figure 1

Canonical and non-canonical binding sites for micro RNA (miRNA) and regulatory RNA (sRNA). Target RNAs can be messenger RNAs (mRNAs) (as shown) or other non-coding RNAs (ncRNAs). The miRNA-Induced Silencing Complex (miRISC), containing at least Argonaute proteins, is required for base pairing between seed sequence of the miRNA and the targeted-RNA. For non-canonical binding sites, the nature of the miRISC is poorly studied. In Enterobacteria, Hfq is involved in the base pairing between sRNA and targeted-RNA, in contrast to sRNAs acting in Gram-positive bacteria that usually possess extended pairing domains. miRNAs and sRNAs bind to their target mRNAs at the 3′-UTR (3′-untranslated regions) or translation initiation sites, respectively. However, miRNAs can also bind at 5′UTRs, sRNAs at 3′UTRs, and both miRNAs and sRNAs within coding sequence regions (arrows). ORF: open reading frame.

Figure 2

Parallels between miRNA and sRNA biogenesis and functions. For miRNA, two enzymes (Drosha and Dicer) are usually required for the biogenesis of a double strand RNA. Only one RNA strand is associated with argonaute protein. The RISC (RNA-induced silencing complex) allows the base pairing with the target (here mRNA) and the recruitment of other proteins involved in translation inhibition and mRNA decay. ‘N’ for nucleus and ‘C’ for cytosol. For sRNA, various RNases (green) can cleave triphosphorylated primary transcripts, and each matured RNA can hold their own functions in stress, metabolism, or virulence. Base-pairing with the target(s) (here mRNA) can be facilitated by dedicated chaperones (orange) than can be followed by target RNA cleavage (red) and/or by modifying translation initiation onto the target mRNA. Both miRNA and sRNA fine-tune gene expression. Note that the sRNA processing steps are not well-examined in many cases and can occur either prior and/or after binding onto their RNA targets.

Figure 3

Epigenetic modifications and functional outcomes for miRNA and sRNA. Several epigenetic modifications might affect miRNA and sRNA functions. The majority of these RNAs are not modified. 3′ mods may promote miRNA decay. Internal mods, especially in the seed region of miRNA, may modify the pairing between miRNA and its targets (RNAs). In basal condition (homeostasis), a miRNA (here in blue) can bind to RNA 1–3. RNA 4 is not targeted by this miRNA. Expression levels of these four RNAs is arbitrarily estimated to 1 in basal condition. The decrease of miRNA amount per cell is associated with a loss or a decrease of miRNA effect on the targets. In other words, a transient upregulation (or de-repression) of the targets could occur in response to 3′ end modifications of miRNAs. This effect is supposed to be transient since usually miRNA are constitutively expressed. In contrast, internal modifications of miRNAs can modify the base-pairing with their targets. Consequently, several targets are regulated by these modified miRNAs and others are no more targeted. These internal modifications might promote the recognition of new targets. Altogether, these modifications alter the canonical repertoire of miRNAs. This type of modifications might favor the adaptation to the environment variations.