Abstract
The establishment of pregnancy in human necessitates appropriate decidualization of stromal cells, which involves steroids regulated periodic transformation of endometrial stromal cells during the menstrual cycle. However, the potential molecular regulatory mechanism underlying the initiation and maintenance of decidualization in humans is yet to be fully elucidated. In this investigation, we document that SOX4 is a key regulator of human endometrial stromal cells decidualization by directly regulating FOXO1 expression as revealed by whole genomic binding of SOX4 assay and RNA sequencing. Besides, our immunoprecipitation and mass spectrometry results unravel that SOX4 modulates progesterone receptor (PGR) stability through repressing E3 ubiquitin ligase HERC4-mediated degradation. More importantly, we provide evidence that dysregulated SOX4-HERC4-PGR axis is a potential cause of defective decidualization and recurrent implantation failure in in-vitro fertilization (IVF) patients. In summary, this study evidences that SOX4 is a new and critical regulator for human endometrial decidualization, and provides insightful information for the pathology of decidualization-related infertility and will pave the way for pregnancy improvement.
Highlights
Adequate crosstalk between implantation-competent embryo and receptive endometrium is prerequisite for successful pregnancy(Cha, Sun et al 2012).The receptive endometrium in human requires remodeling of stromal cells under the regulation of rising progesterone and intracellular cyclic AMP to initiate the decidualization, which will undergo more extensive transformation after embryo implantation (Gellersen and Brosens 2014)
We noted that among the transcription factors expressed in endometrium stromal cells, SOX4 was the 17th highest expressed (Fig. 1A), and as the most abundant member in SOX family (Fig. 1B)
Albeit SOX4 was detected at a low level in the E2-dominant proliferative phase, its expression was progressively increased in the nucleus of stromal cells in P4-dominant early, middle, late secretory phases and this high expression in stroma cell sustained in the decidual cells in early pregnancy (Fig. 1C)
Summary
Adequate crosstalk between implantation-competent embryo and receptive endometrium is prerequisite for successful pregnancy(Cha, Sun et al 2012). The receptive endometrium in human requires remodeling of stromal cells under the regulation of rising progesterone and intracellular cyclic AMP to initiate the decidualization, which will undergo more extensive transformation after embryo implantation (Gellersen and Brosens 2014). We provide evidence that SOX4, under the regulation of P4-PGR, guides human endometrium stromal cells (HESCs) decidualization by regulating FOXO1 expression as revealed by ChIP-Seq and RNA-Seq. Mechanism studies unravel the importance of SOX4 in maintaining the protein stability of PGR by repressing ubiquitin E3 ligase HERC4. Mechanism studies unravel the importance of SOX4 in maintaining the protein stability of PGR by repressing ubiquitin E3 ligase HERC4 Both SOX4 and PGR have been demonstrated to be aberrantly downregulated in the endometrium of EMS patients suffering from implantation failure
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
