Regulatory role for tumor suppressor REST on estrogen receptor (ESR1) expression and leiomyoma pathophysiology

Area of Science:

• Reproductive biology
• Epigenetics
• Molecular endocrinology

Background:

• Uterine fibroids (UL) affect 80% of women by age 50, with unclear pathophysiology.
• Current preclinical models fail to replicate aberrant steroid hormone pathways, hindering therapy development.
• Cultured uterine smooth muscle cells lose estrogen receptor alpha (ESR1) and progesterone receptor (PGR) expression, limiting in vitro studies.

Purpose of the Study:

• Investigate the role of REST (Repressor of silencer element) in epigenetic regulation of UL.
• Determine REST's mechanism in regulating ESR1 and PGR expression.
• Explore REST's potential as a therapeutic target for UL.

Main Methods:

• Chromatin immunoprecipitation (ChIP-PCR and ChIP-seq) in leiomyoma and mouse models.
• Analysis of REST's association with ESR1 and PGR genomic loci.
• Investigated the role of PRICKLE1 (PK1) in REST-mediated ESR1 regulation.

Main Results:

• REST directly binds 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 (PK1).

Conclusions:

• REST plays a significant role in the epigenetic regulation of both ESR1 and PGR in the uterus.
• REST modulation offers a potential strategy to maintain ESR1 expression in cultured cells for mechanistic studies.
• REST is a key epigenetic regulator implicated in uterine leiomyoma pathophysiology.