Myometrial Transcriptional Signatures of Human Parturition

Abstract

The process of parturition involves the transformation of the quiescent myometrium (uterine smooth muscle) to the highly contractile laboring state. This is thought to be driven by changes in gene expression in myometrial cells. Despite the existence of multiple myometrial gene expression studies, the transcriptional programs that initiate labor are not known. Here, we integrated three transcriptome datasets, one novel (NCBI Gene Expression Ominibus: GSE80172) and two existing, to characterize the gene expression changes in myometrium associated with the onset of labor at term. Computational analyses including classification, singular value decomposition, pathway enrichment, and network inference were applied to individual and combined datasets. Outcomes across studies were integrated with multiple protein and pathway databases to build a myometrial parturition signaling network. A high-confidence (significant across all studies) set of 126 labor genes were identified and machine learning models exhibited high reproducibility between studies. Labor signatures included both known (interleukins, cytokines) and unknown (apoptosis, MYC , cell proliferation/differentiation) pathways while cyclic AMP signaling and muscle relaxation were associated with non-labor. These signatures accurately classified and characterized the stages of labor. The data-derived parturition signaling networks provide new genes/signaling interactions to understand phenotype-specific processes and aid in future studies of parturition.

Dynamic transcriptome, accessible genome, and PGR cistrome profiles in the human myometrium

“…Notably, myometrial ZEB1 and PLCL1 mRNA levels both decrease from the term nonlabor to the term labor state, which contrasts with our observations that these two genes exhibit an increase of expression from the NP to the term TP state (Figure ). At the genome‐wide level, 60 of 126 genes that have significant changes of mRNA levels between the term nonlabor and the term labor state either show no change (55 genes) or in an opposite direction (5 genes) of expression in our studies . While this discrepancy could result from data variances of different cohorts of human subjects, it is also possible that these 60 genes could be under tight regulation at the NP, the term nonlabor and the term labor states for potential stage‐specific functions.…”

“…At the genome-wide level, 60 of 126 genes that have significant changes of mRNA levels between the term nonlabor and the term labor state either show no change (55 genes) or in an opposite direction (5 genes) of expression in our studies. 75 While this discrepancy could result from data variances of different cohorts of human subjects, it is also possible that these 60 genes could be under tight regulation at the NP, the term nonlabor and the term labor states for potential stagespecific functions. These observations justify future examinations on the timely change of myometrial transcriptome at multiple states for a high-resolution view of gene expression dynamics.…”

Single Cell Transcriptional Signatures of the Human Placenta in Term and Preterm Parturition

“…Understanding human parturition is essential to tackle the challenge of prematurity, which affects 15 million neonates every year 4–6 . Bulk transcriptomic studies of the cervix 7–11 , myometrium 12–17 , and chorioamniotic membranes 18–20 revealed that labor is a state of physiological inflammation; however, finding specific pathways implicated in preterm labor still remains an elusive goal. A possible explanation is that gestational tissues, and especially the placenta, are heterogeneous composites of multiple cell types, and elucidating perturbations in the maternal-fetal dialogue requires dissection of the transcriptional activity at the cell type level, which is not possible using bulk analyses.…”

Dynamic Transcriptome, Accessible Genome and PGR Cistrome Profiles in the Human Myometrium

“…The present study documents the molecular landscape of the NP and TP myometrium as well as the changes between these two stages. While previous genome-wide studies identify candidate mechanisms for the switch from nonlabor to labor states [40, 75, 76], results presented here report the way the myometrium reorganizes and adapts from nonpregnant to gravid preceding the switch for parturition. This is exemplified by the uniform increase of mRNA of parturition associated genes OXTR, GJA1, ZEB1 and PLCL1 during myometrial remodeling followed by the divergent change of expression patterns (Figure 1).…”