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Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics
BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904357/ https://www.ncbi.nlm.nih.gov/pubmed/27291689 http://dx.doi.org/10.1186/s12916-016-0632-4 |
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author | Migale, Roberta MacIntyre, David A. Cacciatore, Stefano Lee, Yun S. Hagberg, Henrik Herbert, Bronwen R. Johnson, Mark R. Peebles, Donald Waddington, Simon N. Bennett, Phillip R. |
author_facet | Migale, Roberta MacIntyre, David A. Cacciatore, Stefano Lee, Yun S. Hagberg, Henrik Herbert, Bronwen R. Johnson, Mark R. Peebles, Donald Waddington, Simon N. Bennett, Phillip R. |
author_sort | Migale, Roberta |
collection | PubMed |
description | BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human “functional progesterone withdrawal.” This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-016-0632-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4904357 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-49043572016-06-14 Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics Migale, Roberta MacIntyre, David A. Cacciatore, Stefano Lee, Yun S. Hagberg, Henrik Herbert, Bronwen R. Johnson, Mark R. Peebles, Donald Waddington, Simon N. Bennett, Phillip R. BMC Med Research Article BACKGROUND: Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data. METHODS: Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data. RESULTS: We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse. CONCLUSIONS: Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human “functional progesterone withdrawal.” This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-016-0632-4) contains supplementary material, which is available to authorized users. BioMed Central 2016-06-13 /pmc/articles/PMC4904357/ /pubmed/27291689 http://dx.doi.org/10.1186/s12916-016-0632-4 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Migale, Roberta MacIntyre, David A. Cacciatore, Stefano Lee, Yun S. Hagberg, Henrik Herbert, Bronwen R. Johnson, Mark R. Peebles, Donald Waddington, Simon N. Bennett, Phillip R. Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
title | Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
title_full | Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
title_fullStr | Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
title_full_unstemmed | Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
title_short | Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
title_sort | modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904357/ https://www.ncbi.nlm.nih.gov/pubmed/27291689 http://dx.doi.org/10.1186/s12916-016-0632-4 |
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