MicroRNAs in pregnancy

Abstract

Since the discovery of non-coding RNAs, several families of small regulatory molecules have been described including small nucleolar RNAs, piwi-interacting RNAs and microRNAs (miRNAs). MiRNAs are small single-stranded RNA molecules which play an important role in the regulation of gene expression at the transcriptional level. Recent studies demonstrated that about 30% of human genes are regulated by miRNAs and their deregulation has been associated with malignancies and poor outcome. Therefore, it is not surprising that profiling of miRNAs expression and studies on their regulation became a great field of interest in the last decade. However, miRNA-mediated regulation in pregnancy remains poorly investigated although several independent processes associated with placenta development have been shown to be miRNA-regulated. This review provides a general overview of the current data on profiles and functions of microRNAs in the peri-implantation period, embryonic stem cells, placentation and pregnancy, as well as in several pregnancy-related pathologies. We conclude that miRNAs present in the maternal circulation may provide a new promising diagnostic tool for pregnancy disorders.

Introduction

Small non-coding RNAs (ncRNAs) constitute a group of RNAs which do not code for proteins, but instead exercise control over those that do. The first ncRNA was characterized in 1965 in baker's yeast, but the physiological role of ncRNAs was not manifest until 1993 when Lee and colleagues described for the first time the involvement of lin4, a so called “small temporal RNA”, in controlling developmental timing in Caenorhabditis elegans (Lee et al., 1993). It was only in the early 2000s that the term microRNA (miRNA) was introduced and the intracellular mechanisms of RNA interference (RNAi) started to be described. One of the first identified characteristics of the miRNAs was the highly conserved sequences throughout species and the fact that they are expressed in a tissue-specific manner. However, their importance in the control of genome expression became clear when the analysis of miRNA sequences revealed the vast amount of recognition sites on many mRNAs, which suggested a potential role of miRNAs in the control of transcription and translation of protein-coding-RNAs and provided information about the still unexplained 98% of genes which do not produce proteins (Zhang et al., 2007, Buckingham, 2003). It is hypothesised that miRNAs may be key factors in evolutionary processes and particularly in the evolution of the complexity of higher mammals (Bentwich et al., 2005).

During the last decade, about 800 miRNAs have been described in humans and their function in the regulation of cell proliferation and apoptosis in cancer has been demonstrated (Zhang et al., 2007). Currently, most of the miRNA-related studies compare cancer cells versus normal cells, but the analysis of miRNAs in the control of physiological processes including pregnancy is just incipient. Recent reports demonstrate that specific patterns of miRNAs are expressed only in embryonic stem cells and in early phases of embryonic development and some miRNAs are shown to be less strongly expressed in choriocarcinoma cells than in normal trophoblast (Chao et al., 2010, Navarro and Monzo, 2010). More surprisingly, placental miRNAs seem to be released into the maternal circulation and their concentration and patterns in plasma raise the potential for them to become markers for the detection of pregnancy disorders such as fetal growth restriction (FGR) (Mouillet et al., 2010a, Mincheva-Nilsson and Baranov, 2010, Frangsmyr et al., 2005).

In this review, we summarize the current knowledge on miRNA biogenesis, targets and functions with relevance for pregnancy and placental development.