CFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis

Seung Chel Yang, Mira Park, Kwonho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J DeMayo, John P Lydon, David G Skalnik, Hyunjung Jade Lim, Seok‐Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim, Hye Ryun Kim, Haengseok Song
Nature communications · 2023 · vol. 14(1) , pp. 3220 · doi:10.1038/s41467-023-39008-0 · PMID:37270588 · PMC10239508 · W4379260736
article OA: gold CC0 ⤵ 2 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

CFP1 regulates uterine epigenetic landscapes to govern progesterone responses essential for embryo implantation and to suppress endometriosis pathogenesis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This study investigated how the epigenetic regulator CFP1 controls uterine progesterone (P4) responses by profiling chromatin binding (CFP1 ChIP-seq, H3K4me3 ChIP-seq) and gene expression (mRNA-seq) in Cfp1 conditional knockout mice on Day 4 of pseudopregnancy. CFP1 loss impaired P4-dependent uterine responses, prevented embryo implantation (blastocysts accumulated in the oviduct), and produced a failure of decidualization and infertility, with implantation defects persisting even when wildtype blastocysts were transferred to CFP1-deficient uteri; the authors note a caveat that this uses a mouse Pgr-Cre model with uterine-specific deletion. Mechanistically, CFP1-dependent regulation affected uterine transcriptional landscapes both through H3K4me3-dependent decreases and H3K4me3-independent changes, including direct control of P4 response genes (e.g., Gata2, Sox17, Ihh) linked to smoothened signaling, and in a mouse endometriosis model Cfp1-deficient ectopic lesions showed P4 resistance that was rescued by a smoothened agonist, while human endometriosis samples showed CFP1 downregulation. This paper is centrally about endometriosis — it demonstrates that CFP1 regulates P4-epigenome networks underlying P4 resistance in endometriosis through uterine and ectopic lesion models.

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Abstract

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent but also in H3K4me3-independent manners. CFP1 directly regulates important P4 response genes, including Gata2, Sox17, and Ihh, which activate smoothened signaling pathway in the uterus. In a mouse model of endometriosis, Cfp1d/d ectopic lesions showed P4 resistance, which was rescued by a smoothened agonist. In human endometriosis, CFP1 was significantly downregulated, and expression levels between CFP1 and these P4 targets are positively related regardless of PGR levels. In brief, our study provides that CFP1 intervenes in the P4-epigenome-transcriptome networks for uterine receptivity for embryo implantation and the pathogenesis of endometriosis.

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Condition tags

endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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