Receptors for
estrogen and
progesterone frequently interact, via
Cohesin/CTCF loop extrusion, at enhancers distal from regulated genes. Loss-of-function CTCF mutation in >20% of human endometrial
tumors indicates its importance in uterine homeostasis. To better understand how CTCF-mediated enhancer-gene interactions impact endometrial development and function, the Ctcf gene was selectively deleted in female reproductive tissues of mice. Prepubertal Ctcfd/d uterine tissue exhibited a marked reduction in the number of uterine glands compared to those without Ctcf deletion (Ctcff/f mice). Post-pubertal Ctcfd/d uteri were hypoplastic with significant reduction in both the amount of the endometrial stroma and number of glands. Transcriptional profiling revealed increased expression of stem cell molecules Lif, EOMES, and Lgr5, and enhanced
inflammation pathways following Ctcf deletion. Analysis of the response of the uterus to
steroid hormone stimulation showed that CTCF deletion affects a subset of
progesterone-responsive genes. This finding indicates (1)
Progesterone-mediated signaling remains functional following Ctcf deletion and (2) certain
progesterone-regulated genes are sensitive to Ctcf deletion, suggesting they depend on gene-enhancer interactions that require CTCF. The
progesterone-responsive genes altered by CTCF ablation included Ihh, Fst, and Errfi1. CTCF-dependent
progesterone-responsive uterine genes enhance critical processes including anti-
tumorigenesis, which is relevant to the known effectiveness of
progesterone in inhibiting progression of early-stage endometrial
tumors. Overall, our findings reveal that uterine Ctcf plays a key role in
progesterone-dependent expression of uterine genes underlying optimal post-pubertal uterine development.