Estrogen-induced transcription factor EGR1 regulates c-Kit transcription in the mouse uterus to maintain uterine receptivity for embryo implantation. (15th July 2018)

• Record Type: Journal Article
• Authors: Park, Mira; Kim, Hye-Ryun; Kim, Yeon Sun; Yang, Seung Chel; Yoon, Jung Ah; Lyu, Sang Woo; Lim, Hyunjung Jade; Hong, Seok-Ho; Song, Haengseok
• Is Part Of: Molecular and cellular endocrinology. Volume 470(2018)
• Page Start: 75
• Page End: 83
• Publication Date: 2018-07-15
• Subjects: Estrogen -- EGR1 -- c-Kit -- Transcription -- Uterus -- Embryo implantation; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2017.09.033
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Early growth response 1 (Egr1) is a key transcription factor that mediates the action of estrogen (E2 ) to establish uterine receptivity for embryo implantation. However, few direct target genes of EGR1 have been identified in the uterus. Here, we demonstrated that E2 induced EGR1-regulated transcription of c-Kit, which plays a crucial role in cell fate decisions. Spatiotemporal expression of c-Kit followed that of EGR1 in uteri of ovariectomized mice at various time points after E2 treatment. E2 activated ERK1/2 and p38 to induce EGR1, which then activated c-Kit expression in the uterus. EGR1 transfection produced rapid and transient induction of c-KIT in a time- and dose-dependent manner. Furthermore, luciferase assays to measure c-Kit promoter activity confirmed that a functional EGR1 binding site(s) (EBS) was located within −1 kb of the c-Kit promoter. Site-directed mutagenesis and chromatin immunoprecipitation-PCR for three putative EBS within −1 kb demonstrated that the EBS at -818/-805 was critical for EGR1-dependent c-Kit transcription. c-Kit expression was significantly increased in the uterus on day 4 and administration of Masitinib, a c-Kit inhibitor, effectively interfered with embryo implantation. Collectively, our results showed that estrogen induces transcription factor EGR1 to regulate c-Kit transcription for uterine receptivity for embryo implantation in the mouse uterus. Highlights: c-Kit expression was significantly reduced in uteri of Egr1 (−/−) mice. Spatiotemporal expression patterns of c-Kit coincided with those of Egr1 in the uterus after E2 treatment. E2 -ER-dependent activation of the ERK1/2 and p38 MAPK-EGR1 pathway regulated c-Kit induction in the uterus. The EBS at −818/-805 was critical for EGR1-dependent activation of c-Kit transcription. c-Kit expression was significantly increased in mouse uteri receptive for embryo implantation.