Abstract
High throughput sequencing has previously identified differentially expressed genes (DEGs) and enriched signalling networks in human myometrium for term (≥37 weeks) gestation labour, when defined as a singular state of activity at comparison to the non-labouring state. However, transcriptome changes that occur during transition from early to established labour (defined as ≤3 and >3 cm cervical dilatation, respectively) and potentially altered by fetal membrane rupture (ROM), when adapting from onset to completion of childbirth, remained to be defined. In the present study, we assessed whether differences for these two clinically observable factors of labour are associated with different myometrial transcriptome profiles. Analysis of our tissue (‘bulk’) RNA-seq data (NCBI Gene Expression Omnibus: GSE80172) with classification of labour into four groups, each compared to the same non-labour group, identified more DEGs for early than established labour; ROM was the strongest up-regulator of DEGs. We propose that lower DEGs frequency for early labour and/or ROM negative myometrium was attributed to bulk RNA-seq limitations associated with tissue heterogeneity, as well as the possibility that processes other than gene transcription are of more importance at labour onset. Integrative analysis with future data from additional samples, which have at least equivalent refined clinical classification for labour status, and alternative omics approaches will help to explain what truly contributes to transcriptomic changes that are critical for labour onset. Lastly, we identified five DEGs common to all labour groupings; two of which (AREG and PER3) were validated by qPCR and not differentially expressed in placenta and choriodecidua.
Highlights
Understanding how parturition is initiated, how the myometrium is activated to generate the contractions of labour, is essential if we are to reduce rates of adverse maternal and fetal/neonatal outcomes associated with aberrant timing of birth, such as preterm birth and prolonged pregnancy
Human labour can be clinically divided into two distinct phases: (i) ‘early’ phase, which is characterised by cervical effacement, with increasing frequency/intensity of uterine contractions and 3 cm cervical dilatation, and (ii) ‘established’ phase, which is characterised by regular, strong uterine contractions and >3 cm cervical dilatation
Transcriptional changes responsible for initiating uterine contractions to start parturition are more likely to be detected in myometrium samples obtained during early labour, whereas consequential changes are expected to dominate observations for established labour; whether ROM can alter the myometrial transcriptome irrespective of labour status defined by cervical dilatation has not been previously determined
Summary
Understanding how parturition (i.e. the process of birth) is initiated, how the myometrium (uterine smooth muscle) is activated to generate the contractions of labour, is essential if we are to reduce rates of adverse maternal and fetal/neonatal outcomes associated with aberrant timing of birth, such as preterm birth and prolonged pregnancy. Prolonged pregnancy (>41 weeks of gestation; late and post term) is problematic as it increases the risk of stillbirth and significant neonatal morbidity [3]. Current clinical strategies to prevent preterm labour, stop preterm labour after it has started, or induce labour at late/ post term pregnancy are relatively unsuccessful for improving maternal and neonatal outcomes [4, 5]; this is mostly due to our incomplete understanding of the physiological process of term labour and the pathological mechanisms that result in its mistiming. Most published myometrium transcriptome studies [7,8,9,10,11,12,13,14,15,16,17] have compared samples without clear differential analysis for these factors of labour and, in some cases, samples were obtained from women after clinical interventions to artificially augment the process; both shortfalls have potential to obscure the identities of true (i.e. endogenous) labour initiators [18, 19]
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