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Regulatory Role for Tumor Suppressor REST on Estrogen Receptor (ESR1) Expression and Leiomyoma Pathophysiology
Skylar G Bird1, Sumedha Gunewardena1, Ashley S Cloud1
1Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160.
Abstract:
Uterine fibroids, benign tumors of the smooth muscle layer of the uterus, plague approximately 80% of the female population by age 50. While there have been efforts to understand the mechanism behind this pathophysiology, it largely remains unclear. Lack of preclinical animal models that recapitulate aberrant steroid hormone pathways in UL has significantly hampered the development of long-term hormonal therapies for uterine fibroids. In addition, cultured myometrial as well as leiomyoma smooth muscle cells rapidly silence both estrogen receptor alpha (ESR1) and progesterone receptor (PGR) expression through unknown mechanisms, further limiting in vitro mechanistic studies of UL. Previous work by our lab has determined the loss of REST, a master regulator of epigenetic gene silencing, in leiomyoma results in the upregulation of ESR1 targets and therefore estrogen signaling. Using ChIP-PCR, we find REST is directly associated with ESR1 genomic locus, playing a role in its epigenetic regulation. ChIP-seq analysis of Rest cKO mouse uterus samples reveals a global role for REST in the regulation of progesterone receptor target genes and highlights alterations in PGR binding within the Esr1 locus. Additionally, we find REST inhibition of ESR1 expression is regulated through upstream WNT planar cell polarity molecule, PRICKLE1. Based on role of REST in silencing ESR1 expression in cultured myometrial cells, our results support the development of a potential cell culture method to maintain ESR1 expression through REST modulation. Finally, we establish a broad role for REST in epigenetic regulation relevant to leiomyoma pathophysiology.
Insights
Loss of REST in uterine fibroids disrupts estrogen and progesterone signaling. REST’s role in epigenetic regulation offers potential for new cell culture methods and therapies for uterine leiomyoma.
Area of Science:
- Reproductive biology
- Epigenetics
- Molecular endocrinology
Background:
- Uterine leiomyomas (fibroids) affect most women by age 50, with unclear pathophysiology.
- Current preclinical models and in vitro systems struggle to replicate uterine leiomyoma hormone signaling.
- Estrogen receptor alpha (ESR1) and progesterone receptor (PGR) expression is rapidly lost in cultured uterine smooth muscle cells, limiting research.
Purpose of the Study:
- Investigate the role of REST (repressor of silencing) in uterine leiomyoma development and hormone receptor regulation.
- Identify mechanisms by which REST influences ESR1 and PGR expression.
- Explore REST's potential as a therapeutic target and its role in epigenetic regulation of uterine leiomyoma.
Main Methods:
- Chromatin immunoprecipitation (ChIP-PCR and ChIP-seq) in mouse models and cell cultures.
- Analysis of REST association with ESR1 and PGR genomic loci.
- Investigation of PRICKLE1's role in REST-mediated ESR1 regulation.
Main Results:
- REST directly binds to the ESR1 locus, epigenetically regulating its expression.
- Loss of REST in mouse models globally affects PGR target genes and alters PGR binding at the ESR1 locus.
- REST's inhibition of ESR1 is linked to the WNT pathway molecule PRICKLE1.
- REST's function in silencing ESR1 in cultured cells suggests potential for REST modulation to maintain ESR1 expression.
Conclusions:
- REST is a key epigenetic regulator in uterine leiomyoma pathophysiology.
- REST plays a critical role in maintaining normal estrogen and progesterone signaling pathways.
- REST modulation presents a potential strategy for novel cell culture techniques and therapeutic interventions for uterine leiomyoma.
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