NEDD8-mediated neddylation is required for human endometrial stromal proliferation and decidualization

Liao, Yixin; Jiang, Yaling; He, Hui; Ni, Hao; Tu, Z. C.; Zhang, Shuang; Wang, Bingyan; Lou, Jiaoying; Song, Qisheng; Wang, Haibin

doi:10.1093/humrep/dev117

Cited by 40 publications

(39 citation statements)

References 47 publications

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“…Collectively, the screens revealed several expected results, such as FKBP4 (36,44) and NEDD8 (45), showing up as hypoinduced hits (required for decidualization) in the siRNA screen, and prostaglandins (46), showing up as hits in the small-molecule screen (enhance decidualization when added exogenously). While Fig.…”

Section: Discussionmentioning

confidence: 90%

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Haller

Yin

2019

Proc. Natl. Acad. Sci. U.S.A.

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Failure of embryo implantation accounts for a significant percentage of female infertility. Exquisitely coordinated molecular programs govern the interaction between the competent blastocyst and the receptive uterus. Decidualization, the rapid proliferation and differentiation of endometrial stromal cells into decidual cells, is required for implantation. Decidualization defects can cause poor placentation, intrauterine growth restriction, and early parturition leading to preterm birth. Decidualization has not yet been systematically studied at the genetic level due to the lack of a suitable high-throughput screening tool. Herein we describe the generation of an immortalized human endometrial stromal cell line that uses yellow fluorescent protein under the control of the prolactin promoter as a quantifiable visual readout of the decidualization response (hESC-PRLY cells). Using this cell line, we performed a genome-wide siRNA library screen, as well as a screen of 910 small molecules, to identify more than 4,000 previously unrecognized genetic and chemical modulators of decidualization. Ontology analysis revealed several groups of decidualization modulators, including many previously unappreciated transcription factors, sensory receptors, growth factors, and kinases. Expression studies of hits revealed that the majority of decidualization modulators are acutely sensitive to ovarian hormone exposure. Gradient treatment of exogenous factors was used to identify EC50 values of small-molecule hits, as well as verify several growth factor hits identified by the siRNA screen. The high-throughput decidualization reporter cell line and the findings described herein will aid in the development of patient-specific treatments for decidualization-based recurrent pregnancy loss, subfertility, and infertility.

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Section: Discussionmentioning

confidence: 90%

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Haller

Yin

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…The most significant new eQTLs detected include eQTLs for NEDD8, RPS26, SNHG17, SNHG 5 and WARS2 . NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) is a ubiquitin-like protein that targets the ubiquitin E3 ligase family 50 and may be important in regulating normal endometrial function 51 . One study found NEDD8 was expressed in luminal epithelium, glandular epithelium and the stromal cells during the menstrual cycle and that, when inhibited, it significantly decreased proliferation in human endometrial stromal cell lines (HESC) and disrupted decidual transformation 51 .…”

Section: Discussionmentioning

confidence: 99%

Genetic regulation of disease risk and endometrial gene expression highlights potential target genes for endometriosis and polycystic ovarian syndrome

Fung

Mortlock

Girling

et al. 2018

Sci Rep

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Gene expression varies markedly across the menstrual cycle and expression levels for many genes are under genetic control. We analyzed gene expression and mapped expression quantitative trait loci (eQTLs) in endometrial tissue samples from 229 women and then analyzed the overlap of endometrial eQTL signals with genomic regions associated with endometriosis and other reproductive traits. We observed a total of 45,923 cis-eQTLs for 417 unique genes and 2,968 trans-eQTLs affecting 82 unique genes. Two eQTLs were located in known risk regions for endometriosis including LINC00339 on chromosome 1 and VEZT on chromosome 12 and there was evidence for eQTLs that may be target genes in genomic regions associated with other reproductive diseases. Dynamic changes in expression of individual genes across cycle include alterations in both mean expression and transcriptional silencing. Significant effects of cycle stage on mean expression levels were observed for (2,427/15,262) probes with detectable expression in at least 90% of samples and for (2,877/9,626) probes expressed in some, but not all samples. Pathway analysis supports similar biological control of both altered expression levels and transcriptional silencing. Taken together, these data identify strong genetic effects on genes with diverse functions in human endometrium and provide a platform for better understanding genetic effects on endometrial-related pathologies.

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“…2). Indeed, cellular senescence in human endometrial stromal cells is accompanied by impaired decidualization as a consequence of inhibiting neddylation (Liao et al 2015) or suppressing the cAMP mediator, Rap guanine nucleotide exchange factor 3 (RAPGEF3) (Kusama et al 2014), resulting in a phenotype reminiscent of that observed with advanced age. In mice, persistently high levels of senescent cells in uteri by tissue-specific deletion of the tumor protein p53 (Trp53) gene in progesterone receptor-expressing cells also reduced decidual growth without altering the number of implantation sites (Hirota et al 2010).…”

Section: Cellular Senescence and Uterine Agingmentioning

confidence: 99%

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

Velarde

Menon

2016

Journal of Endocrinology

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Cellular senescence is a phenomenon occurring when cells are no longer able to divide even after treatment with growth stimuli. Because senescent cells are typically associated with aging and age-related diseases, cellular senescence is hypothesized to contribute to the age-related decline in reproductive function. However, some data suggest that senescent cells may also be important for normal physiological functions during pregnancy. Herein, we review the positive and negative effects of cellular senescence on female reproductive aging and pregnancy. We discuss how senescent cells accelerate female reproductive aging by promoting the decline in the number of ovarian follicles and increasing complications during pregnancy. We also describe how cellular senescence plays an important role in placental and fetal development as a beneficial process, ensuring proper homeostasis during pregnancy.

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NEDD8-mediated neddylation is required for human endometrial stromal proliferation and decidualization

Abstract: This work was supported in parts by the National Basic Research Program of China (2011CB944400 to H.W.) and the National Natural Science Foundation (81130009, 81330017 to H.W., 81170575 to S.Q. and 31471106 to S.Z.). The author declares that there is no conflict of interest.

Cited by 40 publications

References 47 publications

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Development and utilization of human decidualization reporter cell line uncovers new modulators of female fertility

Genetic regulation of disease risk and endometrial gene expression highlights potential target genes for endometriosis and polycystic ovarian syndrome

Positive and negative effects of cellular senescence during female reproductive aging and pregnancy

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