Junyu Zhai1,2,3, Shang Li1,2, Jingwen Hu1,2, Minzhi Gao1,2, Yun Sun1,2, Zi-Jiang Chen1,2,4,5,6, Linda C Giudice3, Yanzhi Du1,2. 1. Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 2. Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China. 3. Center for Reproductive Sciences, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA. 4. Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. 5. National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Shandong University, Jinan, Shandong, China. 6. Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong, China.
Abstract
CONTEXT: Previous work has demonstrated the role of the circadian clock in ovarian steroid hormone synthesis and attributed embryo implantation failure associated with arrhythmic circadian clock genes to insufficient ovarian-derived progesterone synthesis. Research on expression of core circadian clock genes in the endometrium itself and possible roles in compromised endometrial receptivity and recurrent implantation failure (RIF) are limited. OBJECTIVE: We aimed to assess the core circadian clock gene profiling in human endometrium across the menstrual cycle and the possible gene interaction networks in the endometrial receptivity of window of implantation (WOI) as well as RIF. METHODS: The study was initially an in silico study, with confirmatory lab-based data from primary human endometrial stromal cells (hESCs) as well as endometrial biopsies obtained from 60 women undergoing gynecological surgery in a clinical research center. The study included 30 RIF women and 30 age-matched and body mass index-matched controls. RESULTS: Initial data mining and bioinformatics analysis of human endometrial microarray datasets across the menstrual cycle and between RIF women versus controls demonstrated the varied expression of core circadian clock genes across menstrual cycle, including the key role of PER2 in WOI and RIF. A PER2-centered network was investigated in the regulation of endometrial receptivity. We also confirmed the evidently increased mRNA expression of SHTN1, RXFP1, KLF5, and STEAP4 in the endometrium of RIF women, displaying the same trend as PER2 did, without any changes in MT1E and FKBP5. Treatment of PER2 siRNA in hESCs verified the positive regulation of PER2 to SHTN1, KLF5, and STEAP4. CONCLUSION: Aberrant expression of endometrial PER2 might contribute to impaired endometrial receptivity and development of RIF via regulating SHTN1, KLF5, and STEAP4.
CONTEXT: Previous work has demonstrated the role of the circadian clock in ovarian steroid hormone synthesis and attributed embryo implantation failure associated with arrhythmic circadian clock genes to insufficient ovarian-derived progesterone synthesis. Research on expression of core circadian clock genes in the endometrium itself and possible roles in compromised endometrial receptivity and recurrent implantation failure (RIF) are limited. OBJECTIVE: We aimed to assess the core circadian clock gene profiling in human endometrium across the menstrual cycle and the possible gene interaction networks in the endometrial receptivity of window of implantation (WOI) as well as RIF. METHODS: The study was initially an in silico study, with confirmatory lab-based data from primary human endometrial stromal cells (hESCs) as well as endometrial biopsies obtained from 60 women undergoing gynecological surgery in a clinical research center. The study included 30 RIF women and 30 age-matched and body mass index-matched controls. RESULTS: Initial data mining and bioinformatics analysis of human endometrial microarray datasets across the menstrual cycle and between RIF women versus controls demonstrated the varied expression of core circadian clock genes across menstrual cycle, including the key role of PER2 in WOI and RIF. A PER2-centered network was investigated in the regulation of endometrial receptivity. We also confirmed the evidently increased mRNA expression of SHTN1, RXFP1, KLF5, and STEAP4 in the endometrium of RIF women, displaying the same trend as PER2 did, without any changes in MT1E and FKBP5. Treatment of PER2 siRNA in hESCs verified the positive regulation of PER2 to SHTN1, KLF5, and STEAP4. CONCLUSION: Aberrant expression of endometrial PER2 might contribute to impaired endometrial receptivity and development of RIF via regulating SHTN1, KLF5, and STEAP4.
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