Intragenic MicroRNAs Autoregulate Their Host Genes in Both Direct and Indirect Ways-A Cross-Species Analysis.

Maximilian Zeidler,Alexander Hüttenhofer,Michaela Kress,Kai K Kummer

doi:10.3390/cells9010232

Maximilian Zeidler, Alexander Hüttenhofer + Show 2 more

Open Access

https://doi.org/10.3390/cells9010232

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Journal: Cells	Publication Date: Jan 17, 2020
Citations: 16	License type: CC BY 4.0

Affiliation: Innsbruck Medical University, Universität Innsbruck

Abstract

MicroRNAs (miRNAs) function as master switches for post-transcriptional gene expression. Their genes are either located in the extragenic space or within host genes, but these intragenic miRNA::host gene interactions are largely enigmatic. The aim of this study was to investigate the location and co-regulation of all to date available miRNA sequences and their host genes in an unbiased computational approach. The majority of miRNAs were located within intronic regions of protein-coding and non-coding genes. These intragenic miRNAs exhibited both increased target probability as well as higher target prediction scores as compared to a model of randomly permutated genes. This was associated with a higher number of miRNA recognition elements for the hosted miRNAs within their host genes. In addition, strong indirect autoregulation of host genes through modulation of functionally connected gene clusters by intragenic miRNAs was demonstrated. In addition to direct miRNA-to-host gene targeting, intragenic miRNAs also appeared to interact with functionally related genes, thus affecting their host gene function through an indirect autoregulatory mechanism. This strongly argues for the biological relevance of autoregulation not only for the host genes themselves but, more importantly, for the entire gene cluster interacting with the host gene.

Highlights

All higher eukaryotic genomes harbor protein-coding genes that are required for cellular function, but these resemble only about 1% of the entire genome, whereas 99% do not encode for proteins [1].Within those non-coding regions, non-coding RNAs are embedded, which exert distinct biological roles
(https://www.r-project.org) scripts: miRNAs that are located within the start- and end-coordinates of genes on the same strand were defined as intragenic; miRNAs that are located within genes but on the opposite strand were defined as antisense; miRNAs that are overlapping with genes but are not completely within a gene were defined as overlapping; and miRNAs that were neither intragenic, antisense nor overlapping were defined as extragenic (Figure 1)
Analysis of genomic locations of miRNAs which were mapped onto gene annotations revealed that the majority of miRNAs was located within protein-coding genes, followed by a smaller fraction of miRNAs located on the antisense strand, and a small number of miRNAs at least in part overlapping with a gene

Summary

Introduction

All higher eukaryotic genomes harbor protein-coding genes that are required for cellular function, but these resemble only about 1% of the entire genome, whereas 99% do not encode for proteins [1]. Within those non-coding regions, non-coding RNAs (ncRNAs) are embedded, which exert distinct biological roles. MicroRNAs (miRNAs) are currently the most intensely investigated members of the ncRNA family and are generally accepted as post-transcriptional regulators of gene expression. It has been reported that more than 50% of miRNA-coding genes are located within the extragenic space, thereby possessing their own regulatory elements. The mechanisms regulating the expression of these extragenic miRNAs remain largely elusive. Individual intragenic miRNAs are often co-expressed with their host

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