# Epigenetic Regulation of Myometrial Contractility in Pregnancy and Labor

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $263,542

## Abstract

PROJECT SUMMARY/ABSTRACT
Preterm birth is the leading cause of infant mortality during the first four weeks of life world-wide. The
overarching goal of this research is to enhance our understanding of the genetic and epigenetic mechanisms
that mediate myometrial quiescence and contractility during pregnancy and labor, and their dysregulation
leading to preterm birth. We suggest that progesterone (P4)/progesterone receptor (PR) maintains myometrial
quiescence throughout most of pregnancy by inhibiting expression of inflammatory (e.g. IL-1b, IL-8, COX-2)
and contractile (CAP) (e.g. OXTR, CX43) genes. We propose that this occurs via two basic mechanisms: (1)
PR may tether to transcription factors (e.g. NF-kB, AP-1) bound to promoters of inflammatory genes and
recruit corepressors to inhibit gene expression; (2) PR also may bind directly to promoters of genes encoding
transcriptional repressors (e.g. ZEB1) to activate their expression. ZEB1, in turn, binds to promoters of CAP
genes and recruits a repressive complex to inhibit their expression. By contrast, during the initiation of term
and preterm labor, PR function in myometrium is impaired by its direct interaction with NF-kB, by increased
expression of enzymes that metabolize P4 to inactive products, by decreased expression of PR coactivators
and by upregulation of truncated PR isoforms (e.g. PR-A). The truncated PR isoforms may have reduced
transcriptional and transrepressive activity. We postulate that these changes in inflammatory and CAP gene
expression are mediated by alterations in chromatin modifications and structure. The goals of this proposal are
to define the genes and mechanisms that underlie the inhibitory actions of P4/PR and differential actions of PR-
A and PR-B on inflammatory and CAP gene expression, and to characterize the chromatin modifications that
mediate myometrial quiescence and accompany enhanced CAP and inflammatory gene expression leading to
term and preterm labor. To achieve these goals, we will use mouse models and human myometrial cells and
tissues to: (1) define and characterize components of the complex of transcription factors/coregulators that
interact with PR in the pregnant myometrium to mediate its anti-inflammatory actions and that interact with
ZEB1 to inhibit CAP gene expression; (2) analyze expression and promoter-binding of these PR-interacting
factors during pregnancy and with term and preterm labor and the effects of hormones and microRNAs in their
regulation; (3) use RNA-seq and ChIP-seq to discover myometrial genes that are critical for the maintenance of
pregnancy and initiation of labor and the underlying transcriptional mechanisms for their regulation. RNA-seq
will enable discovery of genes involved in maintenance of pregnancy and the initiation of labor. The combined
use of ChIP-seq will provide global insight into the transcriptional and epigenetic mechanisms that underlie
these gene expression changes. Studies using PR-B-KO mice will elucidate t...

## Key facts

- **NIH application ID:** 10063452
- **Project number:** 5P01HD087150-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** CAROLE R MENDELSON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $263,542
- **Award type:** 5
- **Project period:** 2016-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063452

## Citation

> US National Institutes of Health, RePORTER application 10063452, Epigenetic Regulation of Myometrial Contractility in Pregnancy and Labor (5P01HD087150-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10063452. Licensed CC0.

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