Epigenetic regulation of lncRNA connects ubiquitin-proteasome system with infection-inflammation in preterm births and preterm premature rupture of membranes

Abstract

BackgroundPreterm premature rupture of membranes (PPROM) is responsible for one third of all preterm births (PTBs). We have recently demonstrated that long noncoding RNAs (lncRNAs) are differentially expressed in human placentas derived from PPROM, PTB, premature rupture of the membranes (PROM), and full-term birth (FTB), and determined the major biological pathways involved in PPROM.MethodsHere, we further investigated the relationship of lncRNAs, which are differentially expressed in spontaneous PTB (sPTB) and PPROM placentas and are found to overlap a coding locus, with the differential expression of transcribed mRNAs at the same locus. Ten lncRNAs (five up-regulated and five down-regulated) and the lncRNA-associated 10 mRNAs (six up- and four down-regulated), which were identified by microarray in comparing PPROM vs. sPTB, were then validated by real-time quantitative PCR.ResultsA total of 62 (38 up- and 24 down-regulated) and 1,923 (790 up- and 1,133 down-regulated) lncRNAs were identified from placentas of premature labor (sPTB + PPROM), as compared to those from full-term labor (FTB + PROM) and from premature rupture of membranes (PPROM + PROM), as compared to those from non-rupture of membranes (sPTB + FTB), respectively. We found that a correlation existed between differentially expressed lncRNAs and their associated mRNAs, which could be grouped into four categories based on the gene strand (sense or antisense) of lncRNA and its paired transcript. These findings suggest that lncRNA regulates mRNA transcription through differential mechanisms. Differential expression of the transcripts PPP2R5C, STAM, TACC2, EML4, PAM, PDE4B, STAM, PPP2R5C, PDE4B, and EGFR indicated a co-expression among these mRNAs, which are involved in the ubiquitine-proteasome system (UPS), in addition to signaling transduction and beta adrenergic signaling, suggesting that imbalanced regulation of UPS may present an additional mechanism underlying the premature rupture of membrane in PPROM.ConclusionDifferentially expressed lncRNAs that were identified from the human placentas of sPTB and PPROM may regulate their associated mRNAs through differential mechanisms and connect the ubiquitin-proteasome system with infection-inflammation pathways. Although the detailed mechanisms by which lncRNAs regulate their associated mRNAs in sPTB and PPROM are yet to be clarified, our findings open a new approach to explore the pathogenesis of sPTB and PPROM.

Viral Infection‐Induced Differential Expression of LncRNAs Associated with Collagen in Mouse Placentas and Amniotic Sacs

“…In this case, the epigenetic etiology and pathogenesis should be considered as a candidate approach to investigate the underlying genetic mechanisms. In fact, we have provided evidence that lncRNAs are differentially expressed in placental tissues derived from PTB including PPROM, which contain both maternal and fetal materials and are involved in various biological pathways . These findings indicate that lncRNAs may function as an epigenetic regulator underlying the pathogenic development of PTB, especially for premature labor and premature membrane rupture .…”

“…In fact, we have provided evidence that lncRNAs are differentially expressed in placental tissues derived from PTB including PPROM, which contain both maternal and fetal materials and are involved in various biological pathways . These findings indicate that lncRNAs may function as an epigenetic regulator underlying the pathogenic development of PTB, especially for premature labor and premature membrane rupture . In addition, we have recently determined that the ubiquitin pathway, which was induced by INF‐associated lncRNAs and ubiquitin transcripts, is differentially expressed in human placentas .…”

“…Underscoring the importance of lncRNAs' regulatory roles is their emergence as key players in the etiology of many disease states, especially for complex diseases in which genetic and environmental interactions play key roles . Although lncRNAs have been reported to be involved in many complex human diseases such as neurodegenerative, psychiatric, cardiovascular immunogenic, autoimmune, and carcinogenic, lncRNAs are characterized much less in pregnancy‐related conditions with only a few recently published reports …”

“…In addition, we have recently determined that the ubiquitin pathway, which was induced by INF‐associated lncRNAs and ubiquitin transcripts, is differentially expressed in human placentas . Differential expression of the mRNA transcripts of PPP2R5C, STAM, TACC2, EML4, PAM, PDE4B, STAM, PPP2R5C, PDE4B, and EGFR was correlated with the differential expression of their associated lncRNAs, indicated a co‐expression among mRNAs that are involved in the ubiquitin–proteasome system …”

Long non‐coding RNA regulation of reproduction and development

“…Similarly, a screen in women for lncRNAs associated with premature rupture of the placental membranes (PPROM) identified thirteen lncRNAs that were differentially expressed in PPROM versus full‐term placentae. These lncRNAs appear to play roles in the inflammatory response, smooth muscle contraction, and ligand‐receptor interactions (Luo et al, , ). In a third study, women suffering from polycystic ovary syndrome—characterized by high serum androgens, absence or irregular menstruation, and infertility—the lncRNAs SRAP / SRA1 and CTBP1‐AS1 (carboxy‐terminal binding protein 1, antisense transcript 1) were overexpressed compared to healthy controls (Liu et al, , ).…”