Pregnancy-associated miRNA-clusters

https://doi.org/10.1016/j.jri.2012.11.001Get rights and content

Abstract

MicroRNAs (miRNAs) are expressed in the placenta and can be detected in maternal plasma. An increasing number of studies have been published on the cellular origin, distribution and function of miRNAs in pregnancy. Specific miRNA profiles have been described for the placenta, maternal plasma and several pregnancy disorders. It has been observed that numerous miRNAs, which are predominantly or exclusively expressed during pregnancy, are clustered in chromosomal regions, may be controlled by the same promoters, may have similar seed regions and targets, and work synergistically. The three most eminent clusters are the chromosome 19 miRNA cluster (C19MC), C14MC and miR-371-3 cluster, which is also localized on chromosome 19. MiRNA members of these clusters are not only detected in the placenta, but also in other compartments, e.g. in serum where they have the potential to become novel biomarkers of pregnancy disorders. Additionally, some members are also expressed in a variety of tumors. Antagonism of selected miRNAs or their targets may lead to novel strategies for the development of new drug classes in pregnancy disorders or other diseases. This review summarizes current knowledge on the pregnancy-related miRNA clusters – the C19MC, C14MC and miR-371-3 cluster – in regard to pregnancy and also other, mostly pathological circumstances.

Introduction

The study of gene regulation beyond the DNA transcription has provided important novel interpretations of genetic research and has generated great interest in the field of human reproduction. Epigenetics is defined as the study of changes in gene expression that are not caused by changes in the DNA sequence (Maccani and Marsit, 2009, Wilkins-Haug, 2009). Four main mechanisms are considered as epigenetic processes: DNA methylation, imprinting, histone modification, and small RNA-mediated control, specifically through microRNAs (miRNAs) (Maccani and Marsit, 2009).

MicroRNAs are single-stranded RNA molecules which act as translational repressors by either degrading or inhibiting translation of mRNA targets (reviewed by Morales Prieto and Markert, 2011). miRNAs control numerous cellular processes including metabolism, cell proliferation, apoptosis, and differentiation in almost all cell types (Seitz et al., 2004, Cheng et al., 2005, Bueno et al., 2008, Chen et al., 2010). MiRNAs are known to be involved in processes associated with establishment and maintenance of pregnancy including preparation of the endometrium for implantation (Pan and Chegini, 2008), control of genes associated with inflammatory responses (Chakrabarty et al., 2007), and regulation of immune tolerance-associated genes, such as HLA-G (Veit and Chies, 2009).

During embryogenesis, critical periods are controlled by epigenetic modification of genes: gamete development, preimplantation embryo development, and placentation (Wilkins-Haug, 2009). Recent studies have demonstrated a placenta-specific miRNA profile (Liang et al., 2007), which seems to be dominated by miRNAs expressed in trophoblast cells (Donker et al., 2012, Morales-Prieto et al., 2012). This expression is, at least partly, reflected in the maternal plasma (Chim et al., 2008, Luo et al., 2009) and includes the expression of numerous miRNAs localized within three miRNA clusters: chromosome 14 miRNA cluster (C14MC), C19MC and the miR-371-3 cluster (Liang et al., 2007, Miura et al., 2010, Morales-Prieto et al., 2012). Expression of miRNAs from these clusters changes throughout pregnancy (Miura et al., 2010, Morales-Prieto et al., 2012) and differs among placentas from patients with preterm labor compared to normal term pregnancies (Mayor-Lynn et al., 2011). Remarkably, these clusters are located within imprinted genes which are known to be involved in human embryonic development and to play important roles in the regulation of cellular differentiation and fate (Tsai et al., 2009).

In this review, we summarize the current information about the expression of the pregnancy-related miRNA clusters – C14MC, C19MC and miR-371-3 cluster – their correlation with pregnancy disorders and their possible relevance as biomarkers for the detection and treatment of pregnancy-associated diseases.

Section snippets

The chromosome 14 microRNA cluster (C14MC)

C14MC has also been referred to as the Mirg cluster (Bortolin-Cavaille et al., 2009), the miR-379/miR-410 cluster (Noguer-Dance et al., 2010) or the miR-379/miR-656 cluster (Glazov et al., 2008). It is the largest described miRNA cluster and comprises 52 miRNA genes located within two closely neighboring segments spanning about 40 kb (Fig. 1) (Seitz et al., 2004, Gardiner et al., 2012, Morales-Prieto et al., 2012). Located at the imprinted DLK-DIO3 domain on the human 14q32 chromosomal interval

The chromosome 19 microRNA cluster (C19MC)

C19MC is one of the largest miRNA gene clusters in human, maps to chromosome 19q13.41, and spans a ∼100 kb long region. C19MC miRNAs are primate-specific, conserved in humans and comprise 46 miRNA genes (Fig. 2) (Bentwich et al., 2005, Bortolin-Cavaille et al., 2009, Lin et al., 2010). The C19MC members share common seed sequences and are supposed to be originated from a common ancestor, which might be a member of the miR-371-3 cluster (Zhang et al., 2008).

Similar to C14MC, C19MC is located

The miR-371-3 cluster

The miR-371-3 cluster consists mainly of 3 miRNAs sharing the same seed sequence “AAG UGC”: hsa-miR-371a-3p, hsa-miR-372 and hsa-miR-373-3p. Two miRNAs synthesized from the opposite site of the pre-microRNA (hsa-miR-371-5p and hsa-miR-373-5p), as well as hsa-miR-371b-3p complete the cluster (Griffiths-Jones et al., 2006, Persson et al., 2011). The miR-371-3 cluster in humans is part of a superfamily of miRNAs sharing the same seed sequence, which also includes the mouse homologue cluster

Circulating placenta-derived microRNA as novel biomarkers

MicroRNA profiling of human placenta tissues revealed high expression of the clusters C19MC, C14MC and miR-371-3. Interestingly, their expression changes with the gestational age and even differences between whole and terminal villi can be observed (Luo et al., 2009). Recent reports have demonstrated that the placenta miRNome comprises mostly miRNAs belonging to the C14MC and C19MC in the first and third trimester, respectively (Liang et al., 2007, Morales-Prieto et al., 2012). Further, in situ

MicroRNA clusters, clinical applications and cancer

Human miRNA genes may function as oncogenes and/or tumor suppressors because they are frequently located at fragile genomic regions involved in cancer (Calin et al., 2004). Pregnancy-related miRNAs are not only expressed in pregnancy associated diseases, but their deregulation can also correlate with the development of several tumors. A recent study in neuroblastoma revealed that most of the recurrent large-scale chromosomal imbalances, including loss of C14q, had impact on the miRNA expression

Conclusion and perspectives

Human pregnancy is accompanied by the expression of a large number of pregnancy-related miRNAs. Many of these miRNAs are physiologically expressed almost exclusively in the placenta or in a few fetal tissues. In humans, they are mostly clustered on chromosome 14 (C14MC) and chromosome 19 (C19MC and miR-371-3 cluster). Numerous members of these clusters can be detected in maternal serum and seem to reflect the state of the placenta and might indicate pregnancy disorders. Therefore, there is a

Acknowledgments

DMMP had a Ph.D. grant from the regional graduate academy of the Friedrich-Schiller-University Jena, Germany. WC receives a Ph.D. grant from the German Academic Exchange Service (DAAD). MS is supported by a grant from the interdisciplinary centre for clinical research (IZKF) of the University Hospital Jena, Germany.

References (86)

  • M.R. Suh

    Human embryonic stem cells express a unique set of microRNAs

    Dev. Biol.

    (2004)
  • T.D. Veit et al.

    Tolerance versus immune response – microRNAs as important elements in the regulation of the HLA-G gene expression

    Transpl. Immunol.

    (2009)
  • P.M. Voorhoeve

    A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors

    Cell

    (2006)
  • Q. Yang

    Application of next-generation sequencing technology to profile the circulating microRNAs in the serum of preeclampsia versus normal pregnant women

    Clin. Chim. Acta

    (2011)
  • C. Augello

    MicroRNA profiling of hepatocarcinogenesis identifies C19MC cluster as a novel prognostic biomarker in hepatocellular carcinoma

    Liver Int.

    (2012)
  • E. Bandres

    Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues

    Mol. Cancer

    (2006)
  • M. Bar

    MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries

    Stem Cells

    (2008)
  • I. Bentwich

    Identification of hundreds of conserved and nonconserved human microRNAs

    Nat. Genet.

    (2005)
  • M.L. Bortolin-Cavaille

    C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts

    Nucleic Acids Res.

    (2009)
  • I. Bray

    Widespread dysregulation of miRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival

    PLoS ONE

    (2009)
  • M.J. Bueno

    Control of cell proliferation pathways by microRNAs

    Cell Cycle

    (2008)
  • S. Cairo

    Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • G.A. Calin

    Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • H. Cao

    Evolutionary emergence of microRNAs in human embryonic stem cells

    PLoS ONE

    (2008)
  • A. Chakrabarty

    MicroRNA regulation of cyclooxygenase-2 during embryo implantation

    Proc. Natl. Acad. Sci. U. S. A.

    (2007)
  • A.M. Cheng

    Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis

    Nucleic Acids Res.

    (2005)
  • S.S. Chim

    Detection and characterization of placental microRNAs in maternal plasma

    Clin. Chem.

    (2008)
  • W.J. Cho

    miR-372 regulates cell cycle and apoptosis of ags human gastric cancer cell line through direct regulation of LATS2

    Mol. Cells

    (2009)
  • M.A. Cortez et al.

    MicroRNA identification in plasma and serum: a new tool to diagnose and monitor diseases

    Expert Opin. Biol. Ther.

    (2009)
  • M.E. Crosby

    MicroRNA regulation of DNA repair gene expression in hypoxic stress

    Cancer Res.

    (2009)
  • R.B. Donker

    The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes

    Mol. Hum. Reprod.

    (2012)
  • D.A. Enquobahrie

    Placental microRNA expression in pregnancies complicated by preeclampsia

    Am. J. Obstet. Gynecol.

    (2011)
  • I. Flor et al.

    The dark side of a success story: microRNAs of the C19MC cluster in human tumours

    J. Pathol.

    (2012)
  • F. Fornari

    In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2

    J. Pathol.

    (2012)
  • E. Gardiner

    Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells

    Mol. Psychiatry

    (2012)
  • C.H. Gattolliat

    Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma

    Br. J. Cancer

    (2011)
  • L.A. Genovesi

    Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells

    PLoS ONE

    (2011)
  • J. Gilabert-Estelles

    Role of microRNAs in gynecological pathology

    Curr. Med. Chem.

    (2012)
  • S. Gilad

    Serum microRNAs are promising novel biomarkers

    PLoS ONE

    (2008)
  • E.A. Glazov

    Origin, evolution, and biological role of miRNA cluster in DLK-DIO3 genomic region in placental mammals

    Mol. Biol. Evol.

    (2008)
  • S. Griffiths-Jones

    miRBase: microRNA sequences, targets and gene nomenclature

    Nucleic Acids Res.

    (2006)
  • D. Grun

    MicroRNA target predictions across seven Drosophila species and comparison to mammalian targets

    PLoS Comput. Biol.

    (2005)
  • T.J. Gu

    Alu-directed transcriptional regulation of some novel miRNAs

    BMC Genomics

    (2009)
  • Cited by (201)

    View all citing articles on Scopus
    View full text