Chromatin architectural factor CTCF is essential for progesterone-dependent uterine maturation

Sylvia C. Hewitt, Artiom Gruzdev, Cynthia J. Willson, San Pin Wu, John P. Lydon, Niels Galjart, Francesco J. DeMayo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article numbere23103
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume37
Issue number8
DOIs
Publication statusPublished - Aug 2023

Bibliographical note

Funding Information:
This research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, project Z1AES103311‐01. NIEHS Sequencing Core Lab, NIEHS Histology Core Lab, NIEHS, Immunohistochemistry Core Lab, NIEHS Knockout Mouse Core Lab. We greatly appreciate the bioinformatics advice and training provided by Tianyuan Wang. We appreciate the suggestions and feedback provided by Drs. Kenneth S. Korach and Jackson Hoffman.

Publisher Copyright:
© 2023 Federation of American Societies for Experimental Biology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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