Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression

Area of Science:

• Reproductive Biology
• Epigenetics
• Genomics

Background:

• Hormone-mediated chromatin changes control gene expression.
• Physiological regulation of uterine gene expression by estrogen and progesterone remains unclear.

Purpose of the Study:

• Investigate in vivo dynamics of hormone receptor occupancy, chromatin accessibility, and structure during the mouse estrous cycle.
• Elucidate mechanisms of uterine gene expression regulation by estrogen and progesterone.

Main Methods:

• Combined RNA-seq, ATAC-seq, HiC-seq, and ChIP-seq.
• Analyzed mouse uterus at diestrus (high estrogen) and estrus (high progesterone).
• Performed motif analysis and conditional gene deletion studies.

Main Results:

• Estrogen receptor alpha (ERα) and progesterone receptor (PGR) were unexpectedly co-bound during diestrus and lost during estrus.
• Hypoxia inducible factor 2A (HIF2A) plays a novel role in regulating diestrus gene expression independently of ERα or PGR.
• ERα complexes included PGR and cohesin during diestrus.
• HiC-seq revealed chromatin architecture changes, including enhancer switching, coordinated with receptor binding and HIF2A activity.

Conclusions:

• Uterine gene expression across the estrous cycle is regulated by dynamic ERα and PGR co-binding during diestrus and non-hormone transcription factors like HIF2A during estrus.
• Complex chromatin architecture remodeling is critical for cyclical gene expression.
• Reveals a novel regulatory role for HIF2A in the female reproductive tract.