Aberrant expression of imprinted lncRNA MEG8 causes trophoblast dysfunction and abortion

Abstract

Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs whose nucleotides are longer than 200 bp. Previous studies have shown that they play an important regulatory role in many developmental processes and biological pathways. However, the contributions of lncRNAs to placental development are largely unknown. Here, our study aimed to investigate the lncRNA expression signatures in placental development by performing a microarray lncRNA screen. Placental samples were obtained from pregnant C57BL/6 female mice at three key developmental time points (embryonic day E7.5, E13.5, and E19.5). Microarrays were used to analyze the differential expression of lncRNAs during placental development. In addition to the genomic imprinting region and the dynamic DNA methylation status during placental development, we screened imprinted lncRNAs whose expression was controlled by DNA methylation during placental development. We found that the imprinted lncRNA Rian may play an important role during placental development. Its homologous sequence lncRNA MEG8 (RIAN) was abnormally highly expressed in human spontaneous abortion villi. Upregulation of MEG8 expression in trophoblast cell lines decreased cell proliferation and invasion, whereas downregulation of MEG8 expression had the opposite effect. Furthermore, DNA methylation results showed that the methylation of the MEG8 promoter region was increased in spontaneous abortion villi. There was dynamic spatiotemporal expression of imprinted lncRNAs during placental development. The imprinted lncRNA MEG8 is involved in the regulation of early trophoblast cell function. Promoter methylation abnormalities can cause trophoblastic cell defects, which may be one of the factors that occurs in early unexplained spontaneous abortion.

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“…Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are emerging to play signi cant roles in the epigenetic regulation of trophoblasts cell functions and miscarriage [26,27,28,29,30,31]. These lncRNAs or miRNAs are differentially expressed in the RM villous tissues relative to those in the health control tissues, and they regulate the signaling pathways that are related with the occurrence of miscarriage [32,33].…”

Identification of methylation changes associated with positive and negative growth deviance in Gambian infants using a targeted methyl sequencing approach of genomic DNA

“…RTL1 105 ; MEG8 is a LncRNA involved in the regulation of trophoblast proliferation and invasion, and implicated in spontaneous early abortion 114 and MEG9, a LINC RNA involved in megakaryocyte differentiation and angiogenesis 70 shows genetic association with body mass index and age of menarche. 107 The UPDm (no paternal transcripts: Temple Syndrome) phenotype is characterized by prenataland postnatal growth retardation, neonatal hypotonia, precocious puberty, and facial dysmorphism.…”

“…A further four genes ( MEG3 , RTL1as , MEG8 , and MEG9 ) are all expressed from maternal alleles. MEG3 is a LncRNA affecting growth and development in MEG3 knock‐out mice 113 ; RTL1as is an antisense transcript to the paternally expressed gene RTL1 and encodes a number of microRNAs that may regulate the expression of RTL1 105 ; MEG8 is a LncRNA involved in the regulation of trophoblast proliferation and invasion, and implicated in spontaneous early abortion 114 and MEG9 , a LINC RNA involved in megakaryocyte differentiation and angiogenesis 70 shows genetic association with body mass index and age of menarche 107 …”

IncRNA MEG8 sponging miR-181a-5p contributes to M1 macrophage polarization by regulating SHP2 expression in Henoch Schonlein purpura rats

“…Currently, it is known that functional polarization of macrophages only into M1/M2 groups is an over simpli ed description of macrophage heterogeneity and plasticity, indeed, it is necessary to consider a continuum of functional states [21]. Overall, the current available data indicate that macrophage polarization is a multifactorial process in which a huge number of factors can be involved producing different activation scenarios [22]. Once a macrophage adopts a phenotype, it still retains the ability to continue changing in response to new environmental in uences.…”