# Epigenome, MED12 and Progesterone Action in Uterine Leiomyomas

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2020 · $488,484

## Abstract

Uterine leiomyoma (LM, fibroid) is the most common tumor in women. No long-term medical treatment is
available. Each LM seems to originate from the clonal expansion of a single mutated LM stem cell (LSC) in the
myometrium (MYO). LSC comprise 5% of tumor mass and differentiate into an intermediate cell population
(LIC, 7%), which then become terminally differentiated cells (LDC) comprising 88% of the tumor bulk. Driver
mutations of mediator complex subunit 12 (mut-MED12) occur in 70% of all LM. Progesterone (P4) and its
receptor PR are essential for LM growth. PR-rich LIC transduce P4 signaling to PR-deficient LSC via paracrine
factors to activate their proliferation. Ulipristal acetate (UPA), a PR-selective P4 antagonist, shrank LM and
reduced its symptoms, but its use was halted because of risk of liver injury. Our overall goal is to define the
role of genomewide P4 action in the etiology of mut-MED12‒associated LM tumorigenesis and identify novel
therapeutic targets. We found that mut-MED12 physically interacts with PR and genomewide PR-chromatin
interaction landscapes are dramatically dysregulated in LM expressing mut-MED12 vs. normal MYO tissue
carrying wild type MED12. Mut-MED12 enhances PR recruitment to cis-regulatory elements of P4 target genes
encoding paracrine growth factors, cytokines and extracellular matrix proteins critical for LSC proliferation and
LM tumorigenesis. Furthermore, the uteri of mice with a human-equivalent gain-of-function mutation in Med12
develop LM in response to P4, whereas Med12 knockout blocks P4/PR signaling in mouse uterus. We
hypothesize that mut-MED12 alters PR-chromatin interaction signatures and enhances P4 action in LIC,
providing a support niche for LSC survival and proliferation. Using ChIP-seq, RNA-seq, STARR-seq, and
CRISPR/Cas9-gene editing strategies, and in vivo PDX and mut-Med12 knock-in mouse models, we propose
the following Aims: (1) Determine whether PR-chromatin interaction loci specifically associated with mut-
MED12 stimulate P4 action in a distinct stem-support cell population (LIC), which then send tumorigenic
paracrine signals to increase LSC activity and tumor growth. We will test the hypothesis that mut-MED12
interacts with PR and alters its interaction with chromatin, thereby enhancing P4 responsiveness of LICs to
activate gene transcription and paracrine signaling that support the function of adjacent LSC. (2) Define
whether tumorigenic activity of mut-Med12 is mediated via altering PR-chromatin interaction landscapes in a
human-equivalent mut-Med12 mouse model. We will test the hypothesis that mut-Med12 disrupts chromatin
features surrounding PR-binding sites, thereby supporting gene transcription and pathways critical for LM
tumorigenesis, whereas UPA shrinks LM via altering the aberrant PR-chromatin-epigenomic interactions and
reversing inappropriate expression of disease-associated genes. Deciphering the genomewide mechanisms at
a defined cell population level will help us identi...

## Key facts

- **NIH application ID:** 10005426
- **Project number:** 5P50HD098580-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Serdar E. Bulun
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $488,484
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005426

## Citation

> US National Institutes of Health, RePORTER application 10005426, Epigenome, MED12 and Progesterone Action in Uterine Leiomyomas (5P50HD098580-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10005426. Licensed CC0.

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