The Protein Kinase A Pathway-Regulated Transcriptome of Endometrial Stromal Fibroblasts Reveals Compromised Differentiation and Persistent Proliferative Potential in Endometriosis

Aghajanova, Lusine; Horcajadas, José A.; Weeks, James L.; Esteban, Francisco J.; Nezhat, Camran; Conti, Marco; Giudice, Linda C.

doi:10.1210/en.2009-0923

Cited by 89 publications

(102 citation statements)

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“…Genome-wide analyses revealed a number of genes that are up-regulated or down-regulated by decidualization in human ESCs (5)(6)(7)(8). Gene expression including transcription involves a change of chromatin structure, which can be regulated by epigenetic mechanisms such as histone modifications (9,10).…”

mentioning

confidence: 99%

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

Tamura

Jozaki

Sato

et al. 2018

Journal of Biological Chemistry

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We have previously shown that decidualization of human endometrial stromal cells (ESCs) causes a genome-wide increase in the levels of acetylation of histone-H3 Lys-27 (H3K27ac). We also reported that the distal gene regions, more than 3 kb up or downstream of gene transcription start sites have increased H3K27ac levels. Insulin-like growth factor-binding protein-1 (IGFBP-1) is a specific decidualization marker and has increased H3K27ac levels in its distal upstream region (-4701 bp to -7501 bp). Here, using a luciferase reporter gene construct containing this IGFBP-1 upstream region, we tested the hypothesis that it is an IGFBP-1 enhancer. To induce decidualization, we incubated ESCs with cAMP and found that cAMP increased luciferase expression, indicating that decidualization increased the transcriptional activity from the IGFBP-1 upstream region. Furthermore, CRISPR/Cas9-mediated deletion of this region in HepG2 cells significantly reduced IGFBP-1 expression, confirming its role as an IGFBP-1 enhancer. A ChIP assay revealed that cAMP increased the recruitment of the transcriptional regulators CCAAT enhancer-binding protein β (C/EBPβ), forkhead box O1 (FOXO1), and p300 to the IGFBP-1 enhancer in ESCs. Of note, C/EBPβ knockdown inhibited the stimulatory effects of cAMP on the levels of H3K27ac, chromatin opening, and p300 recruitment at the IGFBP-1 enhancer. These results indicate that the region -4701 to -7501 bp upstream of IGFBP-1 functions as an enhancer for IGFBP-1 expression in ESCs undergoing decidualization, that C/EBPβ and FOXO1 bind to the enhancer region to up-regulate IGFBP-1 expression, and that C/EBPβ induces H3K27ac by recruiting p300 to the IGFBP-1 enhancer.http://www.jbc.org/cgi

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mentioning

confidence: 99%

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

Tamura

Jozaki

Sato

et al. 2018

Journal of Biological Chemistry

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“…8). Thus, lack of SGK1 in the decidua of pregnant mice seems to trigger a series of pathological events that are akin to human miscarriage, including uterine bleeding, early-onset growth restriction and fetal demise.Early human pregnancy events cannot be studied directly, although the decidual response is recapitulated upon differentiation of primary human endometrial stromal cells (HESCs).Furthermore, there is evidence that an aberrant decidual response, associated with reproductive disorders such as endometriosis and RPL, is maintained in culture 27,28 . Thus, to examine the role of SGK1 in human pregnancy failure, we decidualized primary human HESCs from RPL and control subjects over a time-course lasting 8 d (Supplementary Table 1 and Supplementary Fig.…”

mentioning

confidence: 99%

“…Furthermore, there is evidence that an aberrant decidual response, associated with reproductive disorders such as endometriosis and RPL, is maintained in culture 27,28 . Thus, to examine the role of SGK1 in human pregnancy failure, we decidualized primary human HESCs from RPL and control subjects over a time-course lasting 8 d (Supplementary Table 1 and Supplementary Fig.…”

mentioning

confidence: 99%

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

Salker

Christian

Steel

et al. 2011

Nat Med

177

140

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Conflict of interest:The authors have declared that no conflict of interest exists.Nonstandard abbreviations used: SGK1, serum-and glucocorticoid-inducible kinase 1; RPL, recurrent pregnancy loss; ENaC, epithelial sodium channel; HESC, human endometrial stromal cells; ROS, reactive oxygen species; IVF, in vitro fertilization; dpc, days post coitus. 2Infertility and recurrent pregnancy loss (RPL) are prevalent but distinct causes of reproductive failure that often remain unexplained despite extensive investigations 1,2 .Analysis of mid-secretory endometrial samples revealed that SGK1, a kinase involved in epithelial ion transport and cell survival [3][4][5][6] , is upregulated in unexplained infertility, most prominently in the luminal epithelium, but downregulated in the endometrium of women suffering from RPL. To determine the functional significance of these observations, we first expressed a constitutively active SGK1 mutant in the luminal epithelium of the mouse uterus. This prevented expression of certain endometrial receptivity genes, perturbed uterine fluid handling, and abolished embryo implantation.By contrast, implantation was unhindered in Sgk1 -/-mice but pregnancy was often complicated by bleeding at the decidual-placental interface, fetal growth retardation and subsequent demise. Compared to WT animals, pregnancy-dependent induction of genes involved in oxidative stress defenses was grossly impaired in Sgk1 -/-mice. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from RPL subjects and sensitized these cells to oxidative cell death. Thus, depending on the cellular compartment, deregulated SGK1 activity in cycling endometrium interferes with embryo implantation, leading to infertility, or predisposes to pregnancy complications by rendering the feto-maternal interface vulnerable to oxidative damage.The sustained rise in postovulatory circulating progesterone levels renders the endometrium transiently receptive to embryo implantation. This 'window of implantation', confined to 2 to 4 days during the mid-secretory phase of the cycle, enables the embryo to contact and stably adhere to the endometrial luminal epithelium before invading the decidualizing stroma 7-9 . Decidualization, which denotes the transformation of stromal fibroblasts into specialized secretory decidual cells, is indispensable for pregnancy as it governs local immune responses, controls trophoblast invasion, and protects the conceptus against a variety of physiological stressors associated with pregnancy [10][11][12] . Failure of the endometrium to express a receptive phenotype is a major cause of conception delay and IVF 3 treatment failure. On the other hand, perturbations in the maternal decidual response inevitably lead to pregnancy complications, most prevalent of which is miscarriage 2 . SGK1, a serine/threonine protein kinase homologous to AKT, is rapidly induced in response to a rise in progesterone levels in both human and mouse endometrium, first in epithelial cells and then in the decidualizing st...

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“…However, the characterization of the eutopic endometrium from women with endometriosis has also revealed many defects, including altered patterns of angiogenesis, dyssynchrony with the window of implantation as well as ultra structural abnormalities which may contribute to the infertility. Supporting this, isolated endometrial stromal fibroblasts from women with endometriosis do not appear to undergo a normal decidualisation response (Aghajanova et al, 2010), suggesting an impairment of the progesterone-mediated differentiation programme. Specific alterations in the expression molecular markers of endometrial receptivity have also been widely documented, especially the integrin α v β 3 , certain steroid hormone receptors and HOXA10 gene expression, the latter of which has been identified from a genome wide association study of moderate to severe endometriosis as a potential candidate disease locus with proximity to the 7p15.2 SNP association (Painter et al, 2011).…”

Section: Evidence Of Progesterone Resistance In Women With Endometriosismentioning

confidence: 78%

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

Pullen¹

2012

Endometriosis - Basic Concepts and Current Research Trends

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The Protein Kinase A Pathway-Regulated Transcriptome of Endometrial Stromal Fibroblasts Reveals Compromised Differentiation and Persistent Proliferative Potential in Endometriosis

Cited by 89 publications

References 65 publications

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure

Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis

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