RE-1 silencing transcription factor is reduced in endometriosis and uterine deletion in mice alters progesterone responsiveness

Minchella P, Paige Minchella, Vashisht A, Ayushi Vashisht, Riley Peterson, Peterson R, Amanda Graham, Sumedha Gunewardena, Cui W, Wei Cui, Austin Findley, Findley A, Julie A. Christianson, Vargheese Chennathukuzhi, Warren B. Nothnick
bioRxiv : the preprint server for biology · 2026 · doi:10.64898/2026.05.30.728827 · PMID:42282824 · PMC13251921 · W7163342734
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⚙ AI-generated summary by gemini-2.5-flash-lite, 2026-06-06 ⓘ

RE-1 silencing transcription factor (REST) expression is decreased in human endometriosis tissue, and its deletion in mouse uteri impairs progesterone-mediated gene regulation.

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⚙ AI-generated deep summary by claude@2026-07, 2026-07-09 · read from full text ⓘ

This study examined whether reduced RE-1 silencing transcription factor (REST) is involved in impaired progesterone (P4) responsiveness in endometriosis by analyzing human eutopic endometrium and ectopic lesions and by using a uterine-specific Rest conditional knockout mouse model. Immunohistochemistry showed significantly reduced nuclear REST expression in endometriosis tissues, and Rest-deficient mice developed progressive subfertility and hyper-estrogenic uterine features with blunted transcriptional responses to P4 despite preserved P4 receptor expression; REST deficiency also led to larger, less P4-responsive endometriotic-like lesions when induced with experimental endometriosis. The main caveat is that while the mouse model supports a causal role for uterine Rest loss, lesion and pain phenotypes were not uniformly affected (e.g., vaginal hyperalgesia was unchanged, with only modest changes in mechanical sensitivity). This paper is centrally about endometriosis — it identifies decreased nuclear REST in human endometriosis and shows that uterine Rest deletion in mice alters P4 responsiveness and endometriosis-like lesion progression.

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Abstract

UNLABELLED: Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d/d ) mice were generated. Rest d/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis. SIGNIFICANCE STATEMENT: Endometriosis is a common disease in women characterized by altered steroid hormone signaling, infertility, and pelvic pain. RE-1 silencing transcription factor (REST) is a candidate regulator of steroid hormone signaling in gynecologic disease but a role in endometriosis pathophysiology remains unexplored. To fill this knowledge gap, our study utilizes human endometrial and endometriotic tissues coupled with a conditional knockout mouse model for uterine Rest deficiency. We show that REST is significantly reduced in eutopic and ectopic endometrial tissue from women with endometriosis and that deletion from mouse uterine tissue recapitulates clinical characteristics in women with endometriosis including progesterone resistance, sub-fertility and pelvic pain. These findings will further guide future research to understand impaired steroid signaling in the pathophysiology of endometriosis.
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Abstract Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d/d) mice were generated. Rest d/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis. Significance Statement Endometriosis is a common disease in women characterized by altered steroid hormone signaling, infertility, and pelvic pain. RE-1 silencing transcription factor (REST) is a candidate regulator of steroid hormone signaling in gynecologic disease but a role in endometriosis pathophysiology remains unexplored. To fill this knowledge gap, our study utilizes human endometrial and endometriotic tissues coupled with a conditional knockout mouse model for uterine Rest deficiency. We show that REST is significantly reduced in eutopic and ectopic endometrial tissue from women with endometriosis and that deletion from mouse uterine tissue recapitulates clinical characteristics in women with endometriosis including progesterone resistance, sub-fertility and pelvic pain. These findings will further guide future research to understand impaired steroid signaling in the pathophysiology of endometriosis. Competing Interest Statement The authors have declared no competing interest. Footnotes Author Contributions: W.B.N. designed research; P.M., A.V., R.P., A.G. and J.C. conducted research; W.C. and A.F. provided resources, P.M., S.G. and J.C. analyzed data; P.M., A.Y. and W.B.N. wrote the manuscript; W.B.N., W.C., J.A.C., V.C. edited the manuscript. Competing Interest Statement: The authors declare no competing interests.

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