Principles of miRNA–mRNA interactions: beyond sequence complementarity

Abstract

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression by altering the translation efficiency and/or stability of targeted mRNAs. In vertebrates, more than 50% of all protein-coding RNAs are assumed to be subject to miRNA-mediated control, but current high-throughput methods that reliably measure miRNA-mRNA interactions either require prior knowledge of target mRNAs or elaborate preparation procedures. Consequently, experimentally validated interactions are relatively rare. Furthermore, in silico prediction based on sequence complementarity of miRNAs and their corresponding target sites suffers from extremely high false positive rates. Apparently, sequence complementarity alone is often insufficient to reflect the complex post-transcriptional regulation of mRNAs by miRNAs, which is especially true for animals. Therefore, combined analysis of small non-coding and protein-coding RNAs is indispensable to better understand and predict the complex dynamics of miRNA-regulated gene expression. Single-nucleotide polymorphisms (SNPs) and alternative polyadenylation (APA) can affect miRNA binding of a given transcript from different individuals and tissues, and especially APA is currently emerging as a major factor that contributes to variations in miRNA-mRNA interplay in animals. In this review, we focus on the influence of APA and SNPs on miRNA-mediated gene regulation and discuss the computational approaches that take these mechanisms into account.

Literature review of baseline information to support the risk assessment of RNAi‐based GM plants

“…There is a high functional cost of even single nucleotide changes within seed regions, which is consistent with their high sequence conservation among miRNA families both within and between species and suggests processes that may underlie the evolution of miRNA regulatory control (Hill et al, 2014). The target specificity determined by the seed has evolutionary and biological implications because single nucleotide polymorphisms in canonical miRNA binding sites would affect miRNA-mediated regulations, a notion supported also by experimental data (Afonso-Grunz and Muller, 2015;Vosa et al, 2015).The canonical 7nt seed can be divided into several types (Ellwanger et al, 2011). More specifically, the core seeds have been described as a 6-mer (bases 2-7), 7-mer ("7-mer-A1" being bases 1-7, and "7-mer-m8" being bases 2-8), and 8-mer (bases [1][2][3][4][5][6][7][8]; sometimes the 7-mer-A1 and 8-mer seeds are required to have an adenine, 'A', as the first nucleotide types Ellwanger et al, 2011).…”

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

“…In principle, the level of mRNAs in cells is affected by miRNAs, through which the bindings of miRNAs with their dicers degrade mRNAs and weaken their translations (Afonso‐Grunz & Muller, 2015; Beilharz, Humphreys, & Preiss, 2010; Dalmay, 2013; Valinezhad Orang, Safaralizadeh, & Kazemzadeh‐Bavili, 2014). If mRNAs downregulated in the NAc from CUMS‐MDD mice are caused by miRNAs, their correspondent miRNAs will be upregulated, or vice versa.…”

Epigenetic Programming of Cardiovascular Disease by Perinatal Hypoxia and Fetal Growth Restriction

“…This processing leads to a single-strand RNA, which is incorporated into the "proteininduced silencing complex miRNA" (miRISC), which binds to a complementary region in a target mRNA. It has been proposed that a full complementarity between the miRNA and mRNA leads to degradation of the mRNA, while partial complementarity suppresses translation [62].…”

“…Notably, a single miRNA can regulate the expression of multiple mRNAs often associated signaling pathways or metabolic processes, while several miRNAs may converge in the regulation of a single mRNA constituting a complex mechanism for gene expression regulation [61,62].…”