SOX4 facilitates PGR protein stability and FOXO1 expression conducive for human endometrial decidualization
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Evaluation Summary:
Huang et al have identified SOX4 as a key regulatory factor that controls prolactin and FOXO1 transcription factor which in turn regulate decidualization, an important process in embryo development. Further, they have identified that SOX4 also regulates progesterone receptor and dysregulated SOX4-progesterone and ubiquitin ligase HERC4can lead to embryo implantation failure thus explaining the molecular basis of recurrent implantation failure in humans. Overall the study is interesting and the data are very strong. Some concerns noted were the use of immortalized stromal cells, and incomplete nature of studies with human endometrial stroll cells from endometriosis patients, and lack of sufficient discussion in some parts of the text, and whether specific progesterone isofoms are involved downstream of SOX4.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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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.
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Evaluation Summary:
Huang et al have identified SOX4 as a key regulatory factor that controls prolactin and FOXO1 transcription factor which in turn regulate decidualization, an important process in embryo development. Further, they have identified that SOX4 also regulates progesterone receptor and dysregulated SOX4-progesterone and ubiquitin ligase HERC4can lead to embryo implantation failure thus explaining the molecular basis of recurrent implantation failure in humans. Overall the study is interesting and the data are very strong. Some concerns noted were the use of immortalized stromal cells, and incomplete nature of studies with human endometrial stroll cells from endometriosis patients, and lack of sufficient discussion in some parts of the text, and whether specific progesterone isofoms are involved downstream of SOX4.
(This …
Evaluation Summary:
Huang et al have identified SOX4 as a key regulatory factor that controls prolactin and FOXO1 transcription factor which in turn regulate decidualization, an important process in embryo development. Further, they have identified that SOX4 also regulates progesterone receptor and dysregulated SOX4-progesterone and ubiquitin ligase HERC4can lead to embryo implantation failure thus explaining the molecular basis of recurrent implantation failure in humans. Overall the study is interesting and the data are very strong. Some concerns noted were the use of immortalized stromal cells, and incomplete nature of studies with human endometrial stroll cells from endometriosis patients, and lack of sufficient discussion in some parts of the text, and whether specific progesterone isofoms are involved downstream of SOX4.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Huang et al. investigated the role of SOX4 in endometrial stromal cell decidualization. The studies support the conclusion that SOX4 regulates endometrial stromal cell decidualization via enhancing PGR stability. Further, SOX4 deficiency is associated with embryo implantation failure in women with endometriosis that are undergoing IVF treatment. The data are novel and provide new information on how stromal cell decidualization occurs in women. With some exceptions, the quality of the studies is acceptable, and the conclusions are mostly well supported.
Careful review found that some aspects of the experiments need to be clarified and extended. A technical concern is that the studies utilize immortalized cells and overexpression of SOX4 to conduct the ChIP-seq analyses rather than native stromal cells. …
Reviewer #1 (Public Review):
Huang et al. investigated the role of SOX4 in endometrial stromal cell decidualization. The studies support the conclusion that SOX4 regulates endometrial stromal cell decidualization via enhancing PGR stability. Further, SOX4 deficiency is associated with embryo implantation failure in women with endometriosis that are undergoing IVF treatment. The data are novel and provide new information on how stromal cell decidualization occurs in women. With some exceptions, the quality of the studies is acceptable, and the conclusions are mostly well supported.
Careful review found that some aspects of the experiments need to be clarified and extended. A technical concern is that the studies utilize immortalized cells and overexpression of SOX4 to conduct the ChIP-seq analyses rather than native stromal cells. Further, the studies of endometrial stromal cells from endometriosis patients are incomplete.
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Reviewer #2 (Public Review):
Proper development a receptive endometrium is essential to support embryo implantation and successful pregnancy establishment. Huang et.al. uncover the critical role of SOX4 in stromal cell decidualization by RNA-Seq and ChIP-Seq, and have further found that that SOX4 affects the protein stability of progesterone receptor (PGR), which is a master regulator of the decidualization process. In addition, the authors have also identified a direct regulation of SOX4 on the expression of FOSL2, which belong to AP1 complex that are involved in inflammation. The regulation of SOX4 on FOLS2 implicates an alternative role of SOX4 regulating decidualization beyond the PGR signal, which is interesting and opening new avenues for future investigations. Finally, the authors provide compelling evidence that the aberrantly …
Reviewer #2 (Public Review):
Proper development a receptive endometrium is essential to support embryo implantation and successful pregnancy establishment. Huang et.al. uncover the critical role of SOX4 in stromal cell decidualization by RNA-Seq and ChIP-Seq, and have further found that that SOX4 affects the protein stability of progesterone receptor (PGR), which is a master regulator of the decidualization process. In addition, the authors have also identified a direct regulation of SOX4 on the expression of FOSL2, which belong to AP1 complex that are involved in inflammation. The regulation of SOX4 on FOLS2 implicates an alternative role of SOX4 regulating decidualization beyond the PGR signal, which is interesting and opening new avenues for future investigations. Finally, the authors provide compelling evidence that the aberrantly decreased endometrial SOX4 expression is associated with patients with endometriosis and recurrent implantation failure in IVF clinics that showing implantation failure, supporting the clinical relevance of the study and pave way for therapeutic strategies for pregnancy improvement.
The study is overall nicely performed, the data are convincing and overall support the conclusion. Some additional analyses and discussions may further improve the manuscript, as listed separately.
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Reviewer #3 (Public Review):
This study presents a detailed molecular description of an interesting molecular pathway for the understanding of decidualization in health and disease using an experimental design that cover in vitro and in vivo findings including a wide variety of experimental techniques. Conclusions are initially supported by the results obtained. However, the authors should apply more efforts providing more details about experimental design, methodology, and consistency in the structure and flow of the results to ensure their understanding, transparency, and reproducibility. It would be especially valuable to analyse PGR isoforms A and B since PGR-B played a predominant role in hESC decidualization and both isoforms influenced each other's transcriptional activity.
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