Pregnancy-associated miRNA-clusters
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)
Upregulation of human leukocyte antigen-G expression and its clinical significance in ductal breast cancer
Hum. Immunol.
(2010)Abundant expression and hemimethylation of C19MC in cell cultures from placenta-derived stromal cells
Biochem. Biophys. Res. Commun.
(2012)Embryonic stem cell-specific microRNAs
Dev. Cell
(2003)Absolute and relative quantification of placenta-specific microRNAs in maternal circulation with placental insufficiency-related complications
J. Mol. Diagn.
(2012)miR-371-3 expression predicts neural differentiation propensity in human pluripotent stem cells
Cell Stem Cell
(2011)Placental-specific microRNA in maternal circulation – identification of appropriate pregnancy-associated microRNAs with diagnostic potential
J. Reprod. Immunol.
(2011)Computational identification and characterization of primate-specific microRNAs in human genome
Comput. Biol. Chem.
(2010)- et al.
MicroRNAs in pregnancy
J. Reprod. Immunol.
(2011) The levels of hypoxia-regulated microRNAs in plasma of pregnant women with fetal growth restriction
Placenta
(2010)Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia
Am J Obstet Gynecol.
(2007)
Human embryonic stem cells express a unique set of microRNAs
Dev. Biol.
Tolerance versus immune response – microRNAs as important elements in the regulation of the HLA-G gene expression
Transpl. Immunol.
A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors
Cell
Application of next-generation sequencing technology to profile the circulating microRNAs in the serum of preeclampsia versus normal pregnant women
Clin. Chim. Acta
MicroRNA profiling of hepatocarcinogenesis identifies C19MC cluster as a novel prognostic biomarker in hepatocellular carcinoma
Liver Int.
Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues
Mol. Cancer
MicroRNA discovery and profiling in human embryonic stem cells by deep sequencing of small RNA libraries
Stem Cells
Identification of hundreds of conserved and nonconserved human microRNAs
Nat. Genet.
C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts
Nucleic Acids Res.
Widespread dysregulation of miRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival
PLoS ONE
Control of cell proliferation pathways by microRNAs
Cell Cycle
Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer
Proc. Natl. Acad. Sci. U. S. A.
Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers
Proc. Natl. Acad. Sci. U. S. A.
Evolutionary emergence of microRNAs in human embryonic stem cells
PLoS ONE
MicroRNA regulation of cyclooxygenase-2 during embryo implantation
Proc. Natl. Acad. Sci. U. S. A.
Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis
Nucleic Acids Res.
Detection and characterization of placental microRNAs in maternal plasma
Clin. Chem.
miR-372 regulates cell cycle and apoptosis of ags human gastric cancer cell line through direct regulation of LATS2
Mol. Cells
MicroRNA identification in plasma and serum: a new tool to diagnose and monitor diseases
Expert Opin. Biol. Ther.
MicroRNA regulation of DNA repair gene expression in hypoxic stress
Cancer Res.
The expression profile of C19MC microRNAs in primary human trophoblast cells and exosomes
Mol. Hum. Reprod.
Placental microRNA expression in pregnancies complicated by preeclampsia
Am. J. Obstet. Gynecol.
The dark side of a success story: microRNAs of the C19MC cluster in human tumours
J. Pathol.
In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2
J. Pathol.
Imprinted DLK1-DIO3 region of 14q32 defines a schizophrenia-associated miRNA signature in peripheral blood mononuclear cells
Mol. Psychiatry
Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma
Br. J. Cancer
Integrated analysis of miRNA and mRNA expression in childhood medulloblastoma compared with neural stem cells
PLoS ONE
Role of microRNAs in gynecological pathology
Curr. Med. Chem.
Serum microRNAs are promising novel biomarkers
PLoS ONE
Origin, evolution, and biological role of miRNA cluster in DLK-DIO3 genomic region in placental mammals
Mol. Biol. Evol.
miRBase: microRNA sequences, targets and gene nomenclature
Nucleic Acids Res.
MicroRNA target predictions across seven Drosophila species and comparison to mammalian targets
PLoS Comput. Biol.
Alu-directed transcriptional regulation of some novel miRNAs
BMC Genomics
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