The panorama of miRNA-mediated mechanisms in mammalian cells

Abstract

MicroRNAs comprise a large family of short, non-coding RNAs that are present in most eukaryotic organisms and are typically involved in downregulating the expression of protein-coding genes. The detailed mechanisms of miRNA functioning in animals and plants have been under investigation for more than decade. In mammalian cells, miRNA guides the effector complex miRISC to bind with partially complementary sequences, usually within the 3′UTR of mRNAs, and inhibit protein synthesis with or without transcript degradation. In addition to these main mechanisms, several other modes of miRNA-mediated gene expression regulation have been described, but their scale and importance remain a matter of debate. In this review, we briefly summarize the pathway of miRNA precursor processing during miRNA biogenesis and continue with the description of the miRISC assembly process. Then, we present the miRNA-mediated mechanisms of gene expression regulation in detail, and we gather information concerning the proteins involved in these processes. In addition, we briefly refer to the current applications of miRNA mechanisms in therapeutic strategies. Finally, we highlight some of the remaining controversies surrounding the regulation of mammalian gene expression by miRNAs.

Low-Dose Ionizing Radiation Exposure, Oxidative Stress and Epigenetic Programing of Health and Disease

“…Thus, the majority of transcribed genes act as noncoding RNAs, which perform infrastructural (housekeeping role in translation and splicing including ribosomal, transfer and small nuclear RNAs) and regulatory roles (modification of other RNAs by miRNAs, piRNAs, siRNAs, IncRNAs) (46). miRNAs are small (21-25 nt) single-stranded noncoding RNAs that regulate gene expression at the post-transcriptional level by repressing specific mRNAs targets (22,47,48). miRNAs are derived from distinctive hairpin stem loop structures called pre-miRNA.…”

“…RISC binds to 3 0 UTR or target mRNAs and represses target mRNA translation. miRNAs are transcribed independently, in clusters, or as polycistron transcripts (22,48).…”

A simple metric of promoter architecture robustly predicts expression breadth of human genes suggesting that most transcription factors are positive regulators

“…In addition to transcription level regulation (presence/absence of the relevant TFs), genes can be regulated both pre-and post-transcriptionally. Post-transcriptionally, processes such as nonsense-mediated decay (NMD) [7], microRNA level regulation [8], and modulation of RNA stability [9], can also act to reduce the transcript levels below that expected given the transcription rate, potentially buffering larger changes in mRNA levels. Chromatin level pretranscriptional regulation may be the dominant factor [10].…”

Principles of miRNA–mRNA interactions: beyond sequence complementarity

“…Against this backdrop, prediction of miRNA targets in plants requires less elaborate algorithms that mostly rely on sequence complementarity of a given miRNA [35]. Although miRNA binding sites in mammalian cells are also found across the entire mRNA, imperfect 'seed' pairing in 3 0 UTRs is considered to mediate post-transcriptional silencing more efficiently than pairing within the 5 0 UTR or coding sequence [33,36,37]. Consequently, 3 0 UTR heterogeneity caused by SNPs or alternative polyadenylation (APA) strongly impacts miRNA-mediated posttranscriptional regulation and has to be taken into account for prediction of miRNA target sites within these cells.…”