The Role of Cluster C19MC in Pre-Eclampsia Development

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1		Ilona Jaszczuk	--	3059	2022-11-30 05:21:05	\|
2	layout	Sirius Huang	Meta information modification	3059	2022-11-30 05:55:01	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms232213836

Pre-eclampsia is a placenta-related complication occurring in 2–10% of all pregnancies. miRNAs are a group of non-coding RNAs regulating gene expression. There is evidence that C19MC miRNAs are involved in the development of the placenta.

pregnancy pre-eclampsia microRNAs C19MC

1. The Chromosome 19 MicroRNA Cluster (C19MC)

The chromosome 19 microRNA cluster (C19MC) is a primate specific miRNA cluster located on the human chromosome 19q13.41 that is 100 kb in length. It contains 46 tandem repeating microRNA genes encoding 58 mature miRNAs ^[1]^[2]. C19MC is found only in primates and is almost exclusively expressed in the placenta, although low levels have also been shown in embryonic stem cells, testes and some tumors ^[3]^[4]^[5]^[6]. Many publications emphasize that the synthesis of miRNAs is highly orchestrated, and that in the placenta they are expressed at the appropriate time, in a tissue and species manner ^[7]^[8]^[9].

The level of C19MC miRNA expression in plasma and placenta increases with the advancing age of pregnancy, decreasing sharply after delivery ^[10]^[11]. In the plasma of pregnant women, C19MC miRNAs form a part of the placental-related fraction of circulating miRNAs or are packed into exosomes. The source of C19MC miRNAs in the plasma of pregnant women are cells of various areas of the placenta in which cells express C19MC (which can be studied after delivery), and also cells that during remodeling, undergo apoptosis, releasing placental debris and secreting exosomes into the maternal circulation ^[12]^[13].

Exosomes or nanovesicles are a small fraction (30–150 nm) of the extracellular vesicles (EVs) formed in multivesicular bodies (MVBs) ^[14] that are released by most cells into the extracellular space. Their function is to mediate intercellular communication through signaling molecules packed inside and secreted during exocytosis (proteins, lipids, RNA and DNA) after fusion with the cell membrane of target cells. Increased oxidative stress, observed in pre-eclampsia development, predisposes syncytiotrophoblast (STB) cells to the production of more humoral factors and to the release of microvesicles, including exosomes ^[15]^[16]. The composition of the miRNAs transported in exosomes in the PE is different compared to normal pregnancies ^[17]. Extracellular miRNAs packed into exosomes can be responsible for intercellular communication in an autocrine or paracrine manner, and at greater distances through circulation ^[18]^[19]. They can also modulate the immune response that ensures immune tolerance in the mother–fetus relationship or modify pro-inflammatory reactions in the course of pregnancy ^[20]^[21].

C19MC belongs to the genes encoding miRNAs whose expression is influenced by genomic imprinting, an epigenetic mechanism related to monoallelic expression in a parent-of-origin manner. C19MC is expressed exclusively from the paternal allele in the placenta which has been confirmed by single nucleotide polymorphism genotyping (SNP: G or T, rs55765443) mapping upstream the most 5′ microRNA transcribed by C19MC ^[22]. Many C19MC miRNAs are likely formed from the introns of a poorly characterized transcript called ”C19MC-HG”, composed of many repeating non-coding exons ^[1]. C19MC is expressed by the polymerase II promoter region, approximately 17 kb from the first exon, overlapping the differential methylation (DMR) region. The promoter is rich in CpG, showing the maternal characteristic methylation imprint acquired in the oocytes ^[22]. Maternal-specific methylation is deposited at CpG1, here termed ”C19MC-DMR1” (C19MC- differentially methylated region 1).

The structure and function of the C19MC cluster corresponds to features of imprinted genes present in the human genome. Imprinted genes form large chromosomal domains (up to 3 Mb), most of which are expressed in the placenta ^[23]^[24] and play an important role in prenatal embryo or placenta growth or regulate metabolic pathways in the placenta ^[25]^[26]^[27]. Regulation of imprinting gene expression in a given cluster is coordinated by epigenetically modified imprinting control regions (ICRs) that acquire a parental specific male DNA methylation imprint or female germline. In addition, a convergence has been observed between ICRs with maternal imprint and CpG-rich promoter regions ^[28]. DNA methylation at ICRs of imprinted genes is acquired during gametogenesis. Although methylation is a reversible process, the pattern of ICRs’ methylation is refractory to the genome-wide methylation reprogramming that occurs in the embryo after fertilization. DNA methylation levels can also be modified by the presence of specific SNPs ^[29], adjacent to the CpG islands in the in-cis system. It has been shown that C19MC miRNA transcription can be activated in cells by the use of DNA methylation inhibitors, confirming methylation-dependent epigenetic control in this region ^[22]. ICRs are themselves also marked by allele-specific post-translational histones modifications ^[2].

2. The Role of Cluster C19MC in Pre-Eclampsia Development

Chim et al., in 2008, were the first to highlight the potential use of miRNAs as biomarkers of pregnancy complications ^[30]^[31], while the chromosome 19 microRNA cluster (C19MC) was first described by Bentwich et al., in 2005 ^[32]. Noguer-Dance et al., in turn, showed that C19MC microRNAs were clearly expressed during embryo and placenta development. Moreover, they recognized that the imprinted C19MC miRNA genes had to evolve to improve the signaling pathways underlying primate morphology and placental development ^[17]^[22]. Their work also revealed that C19MC dysregulation leads to dysfunctional trophoblast cells, abnormal placentation and the consequent development of PE ^[17]. Zhang et al., in a subsequent study, showed that miR-515-5p was significantly decreased during the differentiation of human syncytiotrophoblasts and significantly increased in the placenta during the development of pre-eclampsia. In contrast, miR-515-5p overexpression inhibited the differentiation of the syncytiotrophoblast ^[33].

Inno et al., in their 2021 research, assessed the expression profile of the human miRNome and the dynamics of its changes in the placenta of pregnant women in three trimesters, and looked for relationships with the occurrence of pregnancy complications. Among the obtained conclusions, they pointed out that most of the C19MC miRNA target genes were involved in cell signaling or transcription regulation important in early pregnancy. Accordingly, two thirds of the C19MC miRNA is expressed especially in the first trimester, is very low in the second trimester and slowly increases in the third trimester ^[29]. Additional research suggested that the advantage of expression primate, paternal-specific C19MC in the first trimester was likely to be associated with a dose-dependent effect on placental transcripts ^[34]^[35].

Hromadnikova et al., on the basis of their conducted research, held that C19MC miRNAs were expressed only in placental tissues (miR-520a, miR-516-5p, miR-517, miR-518b, miR-519a, miR-524-5p, miR-525, miR- 526a, miR-526b, miR-520h) ^[36]^[37]^[38]. They also demonstrated the importance of C19MC in the development of placenta-related complications (pre-eclampsia) and pregnancy hypertension or fetal growth restriction (IUGR) ^[37]. In subsequent studies, Hromadnokova et al. indicated a strong correlation between the increased expression in the first trimester of miR-516-5p, miR-517, and especially miR-520h and miR-518b, and the risk of gestational hypertension ^[39]. The positive correlation between the increase in expression in the first trimester (12–14 hbd) of miR-520a in the serum of pregnant women who developed severe pre-eclampsia was also previously reported by Ura et al. ^[40]. Further studies by Hromadnikova et al. confirmed the increased expression of miR-517-5p, miR-518b and miR-520h in the serum of pregnant women tested in the first trimester (11–13 hbd) who developed pre-eclampsia. Herein, miR-517-5p had the highest predictive value. Unfortunately, no correlation was found between the level of C19MC expression and the risk of IUGR ^[12].

Miura et al. assessed the level of expression miR-520a-5p, miR-520h, miR-516a-5p, miR-516b, miR-518b, miR-519d, miR-525-5p, miR-515-5p, miR-526b, miR-1323 in the plasma of pregnant women at 27–34 weeks of gestation. They observed upregulation of expression of C19MC miRNAs in pregnant women with severe pre-eclampsia (sPE) ^[41]. Jiang et al., in turn, noticed in a patient with sPE, an increased concentration of miR-520g in the serum already in the first trimester ^[42]. In two studies from 2014 and 2015, an inverse correlation between the expression level of miRNAs on C19MC and the weight of the placenta and birth weight of newborns was found ^[41]^[43]. Other researchers have reported that the level of C19MC expression increases with the advancement of pregnancy ^[36]^[38]^[44] and is higher in the case of early onset PE ((PEEO); <34 weeks of gestation) than late onset PE ((PELO); >37 weeks of gestation) ^[43].

Chaiwangyen et al. indicated the importance of miR-519d-3p in the formation of immune tolerance in pregnancy by influencing the proliferation and migration of maternal immune cells (monocytes, granulocytes, T-lymphocytes and NK cells) ^[45]. However, it should be emphasized that humoral factors and miRNAs contained in exosomes also affect the maternal vascular endothelium, stimulating it to release cytokines and activating neutrophil adhesion, and as a result, inducing a systemic inflammatory response characteristic of advanced PE ^[17]. In addition, Delorme Axford et al. clearly indicated that C19MC miRNAs (miR517-3p, miR-512-3p, or 516b-5p) can increase the resistance of maternal cells at the fetal–mother interface to viral infection, by induction of autophagy ^[46]^[47]. Moreover, miR-517a-3p was found to influence the activation of maternal T-lymphocyte and NK cell proliferation, and via the PRKG1 gene, the on activation of the nitric oxide/cGMP signaling pathway ^[47].

Zhao Z. et al., in their review on the use of miRNAs as potential biomarkers for assessing the risk of pregnancy complications, pointed to conflicting data on the expression of individual miRNAs in the various cited studies. As reasons for this, they cited the possible impact of the following heterogeneity factors in patient populations: ethnic origin; variability in the severity of PE; variability of the gestational age; maternal interview; route of delivery or other test conditions: origin and processing samples (tissues, cells, serum and plasma); and data analysis ^[31]. Furthermore, they pointed out that the use of C19MC as a biomarker of pre-eclampsia development is somewhat complicated by the fact that some miRNAs: miR-16; let-7d; miR-520a *; miR-520h; miR-525; miR-516-5p; miR-517 *; and miR-518b are not stable enough during long-term frozen plasma storage ^[48].

In another article from 2019, Hromadnikova et al. indicated a higher predictive value of C19MC miRNAs expression assay using maternal serum exosomes, compared to assaying C19miRNAs expression in whole maternal serum samples. The selected miRNAs expressed only in the placenta with the highest predictive value (miR-516b-5p, miR-517-5p, miR-518b, miR-520a-5p, miR -525-5p) were analyzed in the samples from patients during the first trimester of pregnancy. In patients who subsequently developed GH or PE, decreased expression of miR-517-5p, miR-520a-5p and miR-525-5p was observed. Moreover, decreased expression of miR-520a-5p was found to be correlated with FGR. An important observation is the convergence of the results from maternal serum exosomes with the level of miRNA expression in the postpartum placenta ^[13].

Analysis of the expression level of C19MC miRNAs in placental tissues obtained after delivery also appeared in an earlier original study by Hromadnikova et al., from 2015. The expression of 15 miRNAs was assessed when the research team was attempting to determine correlations with the development of GH, PE, FGF. In the work, correlation was found between the decreased expression of miR-517-5p, miR-519d, miR-520a-5p and miR-525 and the development of GH and between the decreased expression of miR-517-5p, miR-518f-5p, miR-519a, miR-519d, miR-520a-5p and miR-525 and the development of FGF. Accordingly, the development of PE was associated with a decrease in the expression of miR-515-5p, miR-517-5p, miR-518b, miR-518f-5p, miR-519a, miR-519d, miR-520a-5p, miR-520h, miR-524-5p, miR-525 and miR-526a and was more pronounced the longer this complication of pregnancy lasted. Downregulation of miR-519a expression was also found to be strongly associated with development of severe pre-eclampsia (sPE) ^[49].

In contrast, in a study on the analysis of the expression profile of the placental miRNAome in all three trimesters, Inno et al. observed in pregnancies complicated with PE, an increase in the expression of 13 C19MC miRNAs with a negative correlation with gene expression. The strongest correlation was found for the expression of miR-522-5p and miR-518a-5p ^[35].

A careful analysis of the role of individual C19MC miRNAs and their target genes may explain at what stage and how they are involved in the development of pre-eclampsia. Buckberry et al. tried to systematize the knowledge about the importance of the variable expression of C19MC miRNAs in the development of pre-eclampsia through the analysis of selected target genes ^[50]. Their studies consistently showed an increase in expression of eight of the C19MC miRNAs during the development of pre-eclampsia. In addition, it was shown that miR-520g and miR-520h inhibited the expression of VEGF and a simultaneous increase in the expression of the VEGF receptor gene, FLT1, in pre-eclamptic placentas ^[51]. In turn, the importance of increased expression of selected miRNAs C19MC in pre-eclampsia in terms of apoptosis regulation or modification of pro-apoptotic factors is probably related to the CDKN1A (p21) gene. For miR-519b, 519e, miR-520h and possibly miR-517a, the CDKN1A (p21) gene is a target gene ^[52]. CDKN1A (p21) is associated with apoptosis and plays a role as the cell cycle inhibitor.

The correlation between the increase in the expression of C19MC miRNAs in the course of pre-eclampsia, regardless of the time of symptom onset and their severity, is also probably related to target genes, most of which are genes involved in the processes of immune regulation or inflammatory response in the human body ^[53]. When comparing the expression level of C19MC and the level of genes regulated by miRNAs, a negative correlation can be seen. Hromadnikova et al. placed PAPPA among the mentioned target genes, the expression of which is regulated by miR-517 *. In their work, the PAPPA protein was used in the first trimester screening test ^[39].

In further work, upregulated miR-519d was suggested to supposedly silence the expression of MMP2, CXCL6, NR4A2 and FOXL2, and was found to be involved in cellular migration and invasion ^[17]^[54]^[55]. In addition, miR-520g is thought to partially inhibit MMP2 synthesis ^[42], which may lead to impaired remodeling of spiral arteries and thus contribute to the occurrence of PE.

The work of Zhang et al. showed that the target genes for miR-515-5p included hCYP19A1/aromatase, transcription factor glial cells lacking 1 and the WNT receptor ‘frizzled 5’. According to the study, the aforementioned factors played important roles in the process of trophoblast differentiation in early pregnancy ^[33].

Logan et al. pointed out that the Cajal Bodies marker protein (coilin) was a positive regulator of miR-517-3p biogenesis and was induced by hypoxia. Their study suggested that high expression level of miR-517-3p inhibited the translation of TNFAIP3-Interacting Protein 1 (TNIP1), an inhibitor of the NF-kappa B signaling pathway. Moreover, high levels of miR-517-3p and NF-kappa B inhibit trophoblast invasion and increase sFlt-1 secretion at the same time ^[56].

Liu et al. showed that miR-518b stimulated trophoblast cell proliferation via the Rap1b-Ras-MAPK pathway. What is more, an increase in the level of observed miR-518b in the PE placenta may lead to excessive trophoblast proliferation ^[57]. In turn, Canfield et al. investigated the importance of RNA-binding protein LIN28B in the development of PE. They found that there was a decrease in the level of LIN28B in the placenta of women with PE, as compared to normal pregnancies, and that the value of LIN28B was lower the longer the complication lasted ^[58].

In related work, the knockdown of LIN28B in the JEG3 cell line was seen to reduce cell proliferation, suppress the syncytin 1 (SYN-1) involved in syncytiotrophoblast formation and the apelin receptor endogenous ligand (ELABELA), to decrease C19MC miRNA expression (miR516a, miR-516b and miR-519d) and increase mRNA expression ITGb4 and TNF-a, also influencing the process of inflammation in the placenta ^[58]. It is believed that the effect of LIN28 on the regulation of C19MC miRNAs expression results from direct binding to the consensus DNA sequence in the promoter regions, and from activation of CpG TET1 demethylase, as well as from binding to the CpG-rich Alu repeats distributed in C19MC, which act as independent promoters of RNA polymerase III ^[58]^[59]^[60].

Liu et al., in other work, showed that miR-520c-3p could block inflammasome activation and the development of the inflammatory cascade in pre-eclampsia by downgrading NLRP3 expression ^[61]. Xie L. and Sadovsky Y. revealed that miR-519d is a factor that regulated the expression of protein genes involved in the interactions of cells with the extracellular matrix and the processes of migration and thus cell invasion, with no effect on proliferation and apoptosis ^[62]. Of interest in this work is that it demonstrates the importance of the cell migration process in invasion during trophoblast implantation and infiltration, as well as metastasis during neoplasm ^[12]^[42]. The importance of selected C19MC miRNAs in the process of trophoblast development and their modulating effect on the maternal immune response are summarized in Figure 1.

Figure 1. The role of selected C19MC miRNAs in the regulation of trophoblast development and the maternal immune response ^[12]^[28]^[32]^[33]^[35]^[38]^[39]^[45]^[63]^[64]. PRKG1—protein kinase, cGMP- dependent, regulatory, type 1; PAPPA—pappalysin 1, pregnancy-associated plasma protein A; MMP2—matrix metalloproteinase 2; CXCL6—chemokine, CXC motif, ligand 6; NR4A2—nuclear receptor subfamily 4, group A, member 2; FOXL2—forkhead transcription factor FOXL2; hCYP19A1—human cytochrome P450, family 19, subfamily A, polypeptide 1; TNFAIP3—tumor necrosis factor-alpha-induced protein 3; Rap1b-Ras-MAPK pathway-RAS-related protein Rap1b-Ras-mitogen-activated protein kinases pathway; NLRP3—NLR family, pyrin domain-containing 3.

Data from various studies assessing the expression level of C19MC microRNAs in tumors indicate their role in regulating cell proliferation, angiogenesis and possible oncogenic or suppressor activity ^[65]^[66]^[67]. An important common feature of the early stage of placenta development (5–12 hbd) and tumor biology is intense angiogenesis under conditions of relative hypoxia ^[68]^[69].

In some aggressive brain tumors, C19MC amplification has been shown ^[70], while in some thyroid adenomas, the 19q13 region has been involved in chromosomal translocations ^[4]. Depending on the type of tumor, miR-519d has either an oncogenic or a tumor suppressive function ^[71]. Here, oncogenic function is related to miR-519d upregulation and has been demonstrated in hepatocellular carcinoma (HCC) ^[72]^[73], cervical cancer ^[67]^[74] and multiple myeloma ^[75]. In contrast, tumor suppression function was confirmed in hepatocellular carcinoma ^[76], lung adenocarcinoma ^[77], human osteosarcoma ^[78], ovarian cancer ^[79], breast cancer ^[66]^[80] and chondrosarcoma ^[81]. Other studies indicate that the regulatory functions of individual C19MC miRNAs in cancer are related to silencing the expression of factors and signaling pathways related to adhesion, migration, differentiation, growth and angiogenesis (Rap1b, ABCG2, DAPK2, ephrins-EphB2 and EphB4, CXCR4) ^[65]^[66]^[67]^[82]^[83]^[84]^[85].

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Subjects: Obstetrics & Gynaecology

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Dorota Koczkodaj

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1. The Chromosome 19 MicroRNA Cluster (C19MC)

2. The Role of Cluster C19MC in Pre-Eclampsia Development

References