Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Abstract

15 16 Short title: Transcriptomic analysis of severe preterm birth 17 Key words: RNA-seq, preterm birth, gestational age, biomarkers 18 2 19Abstract 20 Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results of 21 the interaction of both genetic and environmental components and constitutes a complex 22 multifactorial syndrome. Transcriptome analysis of PTB has proved challenging because of the 23 multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact 24 to facilitate parturition. A common pathway of labor and PTB may be the activation of fetal 25 membranes. In this work, chorioamnion membranes from severe preterm and term fetus were 26 analyzed using RNA sequencing. A total of 270 genes were differentially expressed (DE): 252 27 were up-regulated and 18 were down-regulated in the severe preterm compared to the term births. 28 We found great gene expression homogeneity in the control samples, and not in severe preterm 29 samples. In this work, we identified up-regulated pathways that were previously suggested as 30 leading to PTB like immunological and inflammatory paths. New pathways that were not 31 identified in preterm like the hemopoietic path appeared up-regulated in preterm membranes. A 32 group of 18 down-regulated genes discriminates between term and severe preterm cases. These 33 genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate 34 genes for understanding the syndrome. Some of the down-regulated genes are involved in the 35 nervous system, morphogenesis (WNT-1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, 36 KCNB1), making them good candidates as biomarkers of PTB.37 The identification of this DE gene pattern may help to develop a multi-gene disease classifier.38 These markers were generated in an admixtured South American population where PTB has a high 39 incidence. Since genetic background may impact differentially in different populations it is 40 mandatory to include populations like South American and African ones that are usually excluded 3 41 from high throughput approaches. These classifiers should be compared to those in other 42 populations to get a global landscape of PTB. 43 44 Introduction 45 Preterm birth (PTB), defined as the delivery of an infant before 37 weeks of completed gestation, 46 is a worldwide health problem and remains the leading cause of global perinatal morbidity and 47 mortality [1][2][3]. PTB is a complex, multifactorial syndrome comprised of multiple clinical 48 subtypes that can be defined as either 'spontaneous' or 'medically indicated' [4,5]. 70 % of PTB 49 cases are idiopathic; 5 % are due to the spontaneous onset of labor (sPTB) and the remaining 25 50 % are consequence of the preterm premature rupture of membranes (PPROM) [5,6]. PTB has also 51 been stratified according to gestational age (GA); neonates born between 24 and 33 weeks (severe 52 PTB) are at higher risk of death, and diseases later in life, than moderate PTB (GA betwee...

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

“…However, the reduction in Tregs at the maternal-fetal interface does not occur in the physiological process of labor at term. This latter finding is in line with the hypothesis that some cases of preterm labor are mediated through a mechanism different from term parturition ( Holt et al, 2011 ; Gomez-Lopez et al, 2017b ; Yellon, 2017 ; Willcockson et al, 2018 ; Paquette et al, 2018 ; Pereyra et al, 2019 ). The most marked reduction of Tregs occurred at the area of contact between the endometrium and the fetal chorioamniotic membranes (i.e., decidua parietalis) in the presence of chronic inflammation of the placenta, which is a pathological process mediated by effector activated T cells ( Kim et al, 2015b ; Arenas-Hernandez et al, 2019 ).…”

LncRNA and transcriptomic analysis of fetal membrane reveal potential targets involved in oligohydramnios

“…Therefore, it is reasonable to speculate that changes in the expression of molecules in the membrane tissue are response to changes in the microenvironment. Many studies have previously provided the molecular information [23][24][25][26] of the fetal membrane tissue. The expression of aquaporin 8 and aquaporin 9 in amniotic membrane of oligohydramnios group is signi cantly lower than that of normal amniotic uid group, however, it has not been shown which lncRNAs regulate the expression of aquaporin 8 and aquaporin 9 in oligohydramnios group [27].…”

Genetics, epigenetics, and transcriptomics of preterm birth

“…Potent technology for transcriptome analysis such as RNA sequencing (RNA‐Seq) can help identify the molecular landscape of preterm birth and improve understanding of the physiology and pathology of term and preterm labor. In an RNA seq study ( n = 24) of placental membranes from severe sPTB (< 33 weeks), multiple inflammatory and immunological pathways were noted to be upregulated 91 . Transcriptomic analyses of preterm infants ( n = 32) born due to infection or sPTB revealed a unique expression signature which included the upregulation of genes in IGF signaling and inflammation pathways.…”