@article{e70f93283ad148ec8adc10994e656cbe,
title = "Delineating differential regulatory signatures of the human transcriptome in the choriodecidua and myometrium at term labor",
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.",
keywords = "Decidua, Endometrium, Gene expression, Immunology, Labor, Molecular biology, Myometrium, Parturition, Pregnancy",
author = "Sylvia Lui and Cyntia Duval and Farkhondeh Farrokhnia and Sylvie Girard and Harris, {Lynda K.} and Tower, {Clare L.} and Adam Stevens and Jones, {Rebecca L.}",
note = "Funding Information: This work was supported by The James Tudor Foundation and Tommy{\textquoteleft}s the Baby Charity. We thank the research midwives at St. Mary{\textquoteright}s Hospital, Manchester, for their invaluable help with subject recruitment and tissue collection, and also to Mrs Helen Bishof for her technical assistance in the in vitro studies. Funding Information: 1Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, University of Manchester, Manchester, UK; 2St Mary{\textquoteright}s Hospital, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; 3Sainte-Justine Hospital Research Centre, Department of Obstetrics and Gynecology, Department of Physiology and Pharmacology, Universite de Montreal, Quebec, Canada and 4School of Pharmacy, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK ∗Correspondence: Maternal and Fetal Health Research Centre, Division of Developmental Biology and Medicine, 5th Floor St Mary{\textquoteright}s Hospital, Oxford Road, Manchester M13 9WL, UK. E-mail: sylvia.lui@manchester.ac.uk †Grant Support: This work was supported by The James Tudor Foundation and Tommy{\textquoteright}s the Baby Charity. The Maternal and Fetal Health Research Centre is supported by Tommy{\textquoteright}s the Baby Charity, an Action Research Endowment Fund, the Manchester BRC and the Greater Manchester CLRN. LKH is supported by a BBSRC David Phillips Research Fellowship. CD and SG are supported by SickKids Foundation and the Canadian Institutes of Health Research Institute of Human Development, Child and Youth Health. ‡Accession Number: GSE9159 Conference Presentation: The findings from this study were presented as a poster at the 62nd annual meeting of the Society for Reproductive Investigation, 25–28 March 2015, San Francisco, California. Edited by Dr. Haibin Wang, PhD, Xiamen University. Publisher Copyright: {\textcopyright} The Author(s) 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved.",
year = "2018",
month = mar,
day = "1",
doi = "10.1093/biolre/iox186",
language = "English (US)",
volume = "98",
pages = "422--436",
journal = "Biology of Reproduction",
issn = "0006-3363",
publisher = "Society for the Study of Reproduction",
number = "3",
}