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10 January 2018 Delineating differential regulatory signatures of the human transcriptome in the choriodecidua and myometrium at term labor
Sylvia Lui, Cyntia Duval, Farkhondeh Farrokhnia, Sylvie Girard, Lynda K. Harris, Clare L. Tower, Adam Stevens, Rebecca L. Jones
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Abstract

Preterm deliveries remain the leading cause of neonatal morbidity and mortality. Current therapies target only myometrial contractions and are largely ineffective. As labor involves multiple coordinated events across maternal and fetal tissues, identifying fundamental regulatory pathways of normal term labor is vital to understanding successful parturition and consequently labor pathologies. We aimed to identify transcriptomic signatures of human normal term labor of two tissues: in the fetal-facing choriodecidua and the maternalmyometrium. Microarray transcriptomic data from choriodecidua and myometrium following term labor were analyzed for functional hierarchical networks, using Cytoscape 2.8.3. Hierarchically high candidates were analyzed for their regulatory casual relationships using Ingenuity Pathway Analysis. Selectedmaster regulators were then chemically inhibited and effects on downstream targets were assessed using real-time quantitative PCR (RT-qPCR). Unbiased network analysis identified upstream molecular components in choriodecidua including vimentin, TLR4, and TNFSF13B. In the myometrium, candidates included metallothionein 2 (MT2A), TLR2, and RELB. These master regulators had significant differential gene expression during labor, hierarchically high centrality in community cluster networks, interactions amongst the labor gene set, and strong causal relationships with multiple downstream effects. In vitro experiments highlighted MT2A as an effective regulator of labor-associated genes. We have identified unique potential regulators of the term labor transcriptome in uterine tissues using a robust sequence of unbiased mathematical and literature-based in silico analyses. These findings encourage further investigation into the efficacy of predicted master regulators in blocking multiple pathways of labor processes across maternal and fetal tissues, and their potential as therapeutic approaches.

Summary Sentence

Combined in silico and in vitro analyses have identified novel transcriptomic regulators of term labor in human choriodecidua and myometrium with further therapeutic potential.

© The Author(s) 2018. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Sylvia Lui, Cyntia Duval, Farkhondeh Farrokhnia, Sylvie Girard, Lynda K. Harris, Clare L. Tower, Adam Stevens, and Rebecca L. Jones "Delineating differential regulatory signatures of the human transcriptome in the choriodecidua and myometrium at term labor," Biology of Reproduction 98(3), 422-436, (10 January 2018). https://doi.org/10.1093/biolre/iox186
Received: 12 July 2017; Accepted: 9 January 2018; Published: 10 January 2018
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