A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition

Jennifer C. Condon, Pancharatnam Jeyasuria, Julie M. Faust, James W. Wilson, Carole R. Mendelson

Research output: Contribution to journalArticle

204 Citations (Scopus)

Abstract

The molecular events that lead to the onset of labor in humans and in other mammalian species remain unclear. We propose that a decline in coactivators containing histone acetylase activity in myometrium may contribute to the onset of labor by impairing the function of the progesterone-progesterone receptor (PR) complex. As assessed by semiquantitative and real-time RT-PCR, immunohistochemistry, and immunoblotting, expression of the PR coactivators cAMP-response element-binding protein (CREB)-binding protein and steroid receptor coactivators 2 and 3 was decreased in fundal uterine tissue of women in labor. Using the mouse as an animal model, we also found decreased coactivator levels in uterine tissues at term. In both human and mouse, the levels of acetylated histone H3 were also decreased in uterine tissues at term. Administration of trichostatin A, a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed the initiation of parturition by 24-48 h, suggesting the functional importance of the decline in histone acetylation in the initiation of labor. These findings suggest that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR function by causing a functional progesterone withdrawal. The resulting decrease in expression of PR-responsive genes should increase sensitivity of the uterus to contractile stimuli.

Original languageEnglish (US)
Pages (from-to)9518-9523
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number16
DOIs
StatePublished - Aug 5 2003

Fingerprint

Progesterone Receptors
Uterus
Histones
Parturition
Acetylation
Labor Onset
Progesterone
Nuclear Receptor Coactivator 2
Nuclear Receptor Coactivator 3
trichostatin A
Histone Acetyltransferases
Cyclic AMP Response Element-Binding Protein
Histone Deacetylase Inhibitors
Myometrium
Immunoblotting
Protein Binding
Real-Time Polymerase Chain Reaction
Carrier Proteins
Animal Models
Immunohistochemistry

Keywords

  • Histone acetylation
  • Human
  • Labor
  • Mouse
  • Pregnancy

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

@article{2ede87b01ba347938992d4c146001cd0,
title = "A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition",
abstract = "The molecular events that lead to the onset of labor in humans and in other mammalian species remain unclear. We propose that a decline in coactivators containing histone acetylase activity in myometrium may contribute to the onset of labor by impairing the function of the progesterone-progesterone receptor (PR) complex. As assessed by semiquantitative and real-time RT-PCR, immunohistochemistry, and immunoblotting, expression of the PR coactivators cAMP-response element-binding protein (CREB)-binding protein and steroid receptor coactivators 2 and 3 was decreased in fundal uterine tissue of women in labor. Using the mouse as an animal model, we also found decreased coactivator levels in uterine tissues at term. In both human and mouse, the levels of acetylated histone H3 were also decreased in uterine tissues at term. Administration of trichostatin A, a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed the initiation of parturition by 24-48 h, suggesting the functional importance of the decline in histone acetylation in the initiation of labor. These findings suggest that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR function by causing a functional progesterone withdrawal. The resulting decrease in expression of PR-responsive genes should increase sensitivity of the uterus to contractile stimuli.",
keywords = "Histone acetylation, Human, Labor, Mouse, Pregnancy",
author = "Condon, {Jennifer C.} and Pancharatnam Jeyasuria and Faust, {Julie M.} and Wilson, {James W.} and Mendelson, {Carole R.}",
year = "2003",
month = "8",
day = "5",
doi = "10.1073/pnas.1633616100",
language = "English (US)",
volume = "100",
pages = "9518--9523",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "16",

}

TY - JOUR

T1 - A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition

AU - Condon, Jennifer C.

AU - Jeyasuria, Pancharatnam

AU - Faust, Julie M.

AU - Wilson, James W.

AU - Mendelson, Carole R.

PY - 2003/8/5

Y1 - 2003/8/5

N2 - The molecular events that lead to the onset of labor in humans and in other mammalian species remain unclear. We propose that a decline in coactivators containing histone acetylase activity in myometrium may contribute to the onset of labor by impairing the function of the progesterone-progesterone receptor (PR) complex. As assessed by semiquantitative and real-time RT-PCR, immunohistochemistry, and immunoblotting, expression of the PR coactivators cAMP-response element-binding protein (CREB)-binding protein and steroid receptor coactivators 2 and 3 was decreased in fundal uterine tissue of women in labor. Using the mouse as an animal model, we also found decreased coactivator levels in uterine tissues at term. In both human and mouse, the levels of acetylated histone H3 were also decreased in uterine tissues at term. Administration of trichostatin A, a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed the initiation of parturition by 24-48 h, suggesting the functional importance of the decline in histone acetylation in the initiation of labor. These findings suggest that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR function by causing a functional progesterone withdrawal. The resulting decrease in expression of PR-responsive genes should increase sensitivity of the uterus to contractile stimuli.

AB - The molecular events that lead to the onset of labor in humans and in other mammalian species remain unclear. We propose that a decline in coactivators containing histone acetylase activity in myometrium may contribute to the onset of labor by impairing the function of the progesterone-progesterone receptor (PR) complex. As assessed by semiquantitative and real-time RT-PCR, immunohistochemistry, and immunoblotting, expression of the PR coactivators cAMP-response element-binding protein (CREB)-binding protein and steroid receptor coactivators 2 and 3 was decreased in fundal uterine tissue of women in labor. Using the mouse as an animal model, we also found decreased coactivator levels in uterine tissues at term. In both human and mouse, the levels of acetylated histone H3 were also decreased in uterine tissues at term. Administration of trichostatin A, a specific and potent histone deacetylase inhibitor, to pregnant mice late in gestation increased histone acetylation and delayed the initiation of parturition by 24-48 h, suggesting the functional importance of the decline in histone acetylation in the initiation of labor. These findings suggest that the decline in PR coactivator expression and in histone acetylation in the uterus near term may impair PR function by causing a functional progesterone withdrawal. The resulting decrease in expression of PR-responsive genes should increase sensitivity of the uterus to contractile stimuli.

KW - Histone acetylation

KW - Human

KW - Labor

KW - Mouse

KW - Pregnancy

UR - http://www.scopus.com/inward/record.url?scp=0041923549&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0041923549&partnerID=8YFLogxK

U2 - 10.1073/pnas.1633616100

DO - 10.1073/pnas.1633616100

M3 - Article

VL - 100

SP - 9518

EP - 9523

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 16

ER -