Conditional deletion of Sox17 reveals complex effects on uterine adenogenesis and function

Guimarães-Young, Amy; Neff, T.; Dupuy, Adam J.; Goodheart, Michael J.

doi:10.1016/j.ydbio.2016.04.010

Cited by 37 publications

(35 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6B) that consists of GATA2, PGR and SOX17 transcription factors (Guimaraes-Young et al, 2016; Hirate et al, 2016; Rubel et al, 2012a; Rubel et al, 2012b). To investigate this network in human endometrial samples, we performed path analyses on the GSE58144 dataset using a structural equation modeling (Xiong et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…In this group, the binding motif for Forkhead box (FOX) proteins is enriched in the GATA2 occupying sites, which bears a resemblance of co-occupancy of GATA2 and FOXA1 in genomic loci of AR target genes in prostate cancer (Wu et al, 2014). Furthermore, the enrichment of SOX (Sex Determining Region Y Box) factor binding motifs also implicates a potential interaction between GATA2 and other uterine transcription regulators such as SOX17 (Garcia et al, 2007; Guimaraes-Young et al, 2016; Hirate et al, 2016). These results indicate future investigations on potential mechanisms by which GATA2 and PGR work independently with other transcription regulators to direct gene expression in the uterus.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

et al. 2016

View full text Add to dashboard Cite

SUMMARY Altered progesterone responsiveness leads to female infertility and cancer, but underlying mechanisms remain unclear. Mice with uterine-specific ablation of Gata2 are infertile showing failures in embryo implantation, endometrial decidualization and uninhibited estrogen signaling. Gata2 deficiency results in reduced progesterone receptor (PGR) expression and attenuated progesterone signaling, as evidenced by genome-wide expression profiling and chromatin immunoprecipitation. GATA2 not only occupies at and promotes expression of Pgr, but also regulates downstream progesterone responsive genes in conjunction with the PGR. Additionally, Gata2 knockout uteri exhibit abnormal luminal epithelia with ectopic TRP63 expressing squamous cells and a cancer related molecular profile in a progesterone independent manner. Lastly, we found a conserved GATA2-PGR regulatory network in both human and mouse, based on gene signature and path analyses using gene expression profiles of human endometrial tissues. In conclusion, uterine Gata2 regulates a key regulatory network of gene expression for progesterone signaling at the early pregnancy stage.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In the present study, FOXA2 binding intervals unique to P-phase endometrium contained SOX17, ESR1, ELK1, and nuclear receptor subfamily 4 group A member 2 TFBS motifs; all of those transcription factors are expressed in the GE of the human uterus, and their expression decreases in the MS phase based on RNA-Seq analysis. Of note, Sox17-conditional knockout mice lack uterine glands, indicating a possible reciprocal interaction between Sox17 and Foxa2 (49). Although glands initially develop in neonatal Esr1-null mice, Esr1 is required for maintenance of differentiated GE before puberty and GE function in the adult mouse uterus (46).…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

et al. 2019

View full text Add to dashboard Cite

The pioneer forkhead box (FOX)A2 transcription factor is specifically expressed in the glands of the uterus, which are central to endometrial function and fertility. In mice, FOXA2 is a critical regulator of uterine gland development in the neonate and gland function in the adult. An integrative approach was used here to define the FOXA2 cistrome in the human endometrium. Genome‐wide mapping of FOXA2 binding intervals by chromatin immunoprecipitation sequencing was performed using proliferative (P)‐ and midsecretory (MS)‐phase endometrium and integrated with the transcriptome determined by RNA sequencing. Distinctive FOXA2 binding intervals, enriched for different transcription factor binding site motifs, were detected in the P and MS endometrium. Pathway analysis revealed different biologic processes regulated by genes with FOXA2 binding intervals in the P and MS endometrium. Thus, FOXA2 is postulated to regulate gene expression in concert with other transcription factors and impact uterine gland development and function in a cycle phase–dependent manner. Analyses also identified potential FOXA2‐regulated genes that influence uterine receptivity, blastocyst implantation, and stromal cell decidualization, which are key events in pregnancy establishment.—Kelleher, A. M., Behura, S. K., Burns, G. W., Young, S. L., DeMayo, F. J., Spencer, T. E. Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium. FASEB J. 33, 8543–8554 (2019). http://www.fasebj.org

show abstract

“…These ewes are infertile (3,5), suggesting that uterine glands are required for conceptus survival and development. Adenogenesis is associated with several signaling pathways and their development and maturation has been linked with growth factors, Wnt signaling, and homeobox signaling pathways (6,7).…”

mentioning

confidence: 99%

Hunting for Fox(A2): Dual roles in female fertility

Cha

Dey

2017

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

View full text Add to dashboard Cite

Pregnancy encompasses a complex orchestration of several sequential steps across tissue and cell types in the mother and fetus for embryo development and delivery of offspring at an opportune time for survival. These steps include embryo implantation, stromal cell proliferation and differentiation (decidualization), placentation, and ultimately parturition with delivery of offspring (1, 2). The outcome of each stage depends on the success of the preceding stages. Most pregnancy events in mice and other mammals are primarily regulated by ovarian estrogen and progesterone (2), yet the molecular discourse between the reproductive system and the embryo that guides pregnancy events is a prevailing mystery. The uterus is primarily comprised of two compartments: the outermost muscle layer (myometrium) and the underlying endometrium. The endometrium is composed of the stroma, the epithelium, and glands. These glands have been seen throughout pregnancy and are acknowledged as essential for implantation and pregnancy success (3), yet their formation and particular genetic and molecular contributions during distinct stages of pregnancy have not been fully appreciated. In PNAS, Kelleher et al. (4) show that Forkhead box a2 (FOXA2), a transcription factor expressed in neonatal and adult mouse uteri, plays dual, stage-specific roles in maternal tissues during pregnancy (Fig. 1).The development of glands (adenogenesis) begins in the postnatal uterus, and their maturation and differentiation is under endocrine control during adulthood. Gland formation and secretions during pregnancy are essential for successful reproduction in mammals. Uterine gland knockout ewes do not form glands, nor do they cycle. These ewes are infertile (3, 5), suggesting that uterine glands are required for conceptus survival and development. Adenogenesis is associated with several signaling pathways and their development and maturation has been linked with growth factors, Wnt signaling, and homeobox signaling pathways (6, 7).FoxA2 is a homeobox transcription factor required during embryogenesis and plays multiple critical roles in gastrulation, neural tube patterning, and gastrointestinal development (8, 9). FoxA2 is also expressed in glands in the pregnant mouse uterus, suggesting its role in pregnancy (10). Because systemic deletion of FoxA2 results in embryonic lethality, its role was evaluated during pregnancy by transgenic mice with FoxA2 conditionally ablated in the mouse uterus (10, 11). These mice had significantly reduced fertility with smaller litter sizes as a result of disrupted embryo implantation. Blastocysts in mutant females could attach to the uterine luminal epithelium (LE) with appropriate expression of uterine receptivity marker genes. However, the embryo could not penetrate the LE for implantation or initiate stromal cell decidual responses in most of the females studied. The number of endometrial glands was severely reduced in FoxA2 mutant mice, precluding the secretion of leukemia inhibitory factor (Lif) expression, a critical fac...

show abstract

Conditional deletion of Sox17 reveals complex effects on uterine adenogenesis and function

Cited by 37 publications

References 27 publications

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

A Gata2-Dependent Transcription Network Regulates Uterine Progesterone Responsiveness and Endometrial Function

Integrative analysis of the forkhead box A2 (FOXA2) cistrome for the human endometrium

Hunting for Fox(A2): Dual roles in female fertility

Contact Info

Product

Resources

About