Dysregulated proliferation and immune response induced by estrogen in Egr1 knockout uterus are similar to those in immature uterus.

BACKGROUND

A balance between estrogen (E2) and progesterone (P4) is vital for a successful pregnancy, and an imbalance between these two hormones yields female infertility. E2 mediates uterine receptivity and regulates endometrial growth, the immune system, and hormone signaling by rapidly inducing early growth response 1 (EGR1). However, the precise mechanism by which EGR1 regulates E2-mediated uterine growth remains unclear. This study examined the transcriptional signatures of ovariectomized (OVX) Egr1 knockout (KO) mice compared to those of wild-type (WT) mice to clarify the function of EGR1 in the E2-dependent uterine response.

RESULTS

Egr1 KO uteri exhibited an impaired E2 response, with significant changes in the expression of the key genes Bgn, c-Kit, Ripor2, and Arg2. During early E2 response, Egr1 KO uteri showed upregulated insulin-like growth factor (IGF) signaling pathway genes and downregulated reproduction-related genes. During late E2 response, Egr1 KO uteri showed enhanced proliferative processes, such as DNA replication and mitotic cell cycle phase transition, potentially related to poly-ADP ribosylation (PARylation), along with a reduction in immune response. Notably, the transcriptional signatures in mature OVX Egr1 KO uteri resembled those in immature uteri, with similar increases in proliferation and decreases in immune response at the pathway level.

CONCLUSIONS

Our findings indicate that EGR1 is essential for regulating immune response and uterine proliferation via IGF signaling and PARylation, and acts as a gatekeeper transcription factor that mediates E2 actions in the mature uterus. Notably, we found that the transcriptional signatures of EGR1 in mature uteri overlapped with the primary E2 function and suggested a novel concept that these transcriptional signatures in mature Egr1 KO uteri are similar to those of immature uteri. Our findings offer novel insights into the role of EGR1 as an E2 mediator in the uterus at the molecular level.