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Fetal brain elicits sexually conflicting transcriptional response to the deficiency of uterine Forkhead Box A2 (Foxa2) in mice

ABSTRACT: RNA-seq identified different gene sets relating to biological functions such as aging, longevity, and nutrient sensing and signaling that were regulated in a sex-biased manner between the placenta and fetal brain. Conditional knockout of the transcription factor Forkhead Box A2 (Foxa2) in the uterus elicited sexual conflicting expression of those genes between the placenta and fetal brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE157555 | GEO | 2021/10/06

REPOSITORIES: GEO

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Sexually dimorphic effects of forkhead box a2 (FOXA2) and uterine glands on decidualization and fetoplacental development

Project description:Glands of the uterus are essential for the establishment of pregnancy in mice, sheep and likely humans. Forkhead box a2 (FOXA2) is expressed specifically in the glands of the uterus and a critical regulator of glandular epithelium (GE) differentiation, development and function. Mice with a conditional deletion of FOXA2 in the adult uterus, created using the lactotransferrin iCre (Ltf-iCre) model, have a morphologically normal uterus with glands, but lack a considerable number of FOXA2-dependent GE-expressed genes. Adult FOXA2 conditional knockout (cKO; Ltf-iCre:Foxa2 flox) mice are infertile due to defective embryo implantation arising from a lack of leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin. Intraperitoneal injections of LIF can initiate embryo implantation in the uterus of adult FOXA2 cKO mice with pregnancies maintained to term. Here, we tested the hypothesis that FOXA2-regulated genes in the uterine glands impact development of the decidua, placenta and fetus. On gestational day (GD) 8.5, the anti-mesometrial and mesometrial decidua transcriptome was noticeably altered in FOXA2 cKO mice. Viable fetuses were reduced in FOXA2 cKO mice on GDs 12.5 and 17.5. Sex-dependent differences in fetal weight, placenta histoarchitecture, and the placenta and metrial gland transcriptome were observed between control and FOXA2 cKO mice. The transcriptome of the placenta with a female fetus was considerably more altered than the placenta with a male fetus in FOXA2 cKO dams. These studies reveal previously unrecognized sexually dimorphic effects of FOXA2 and uterine glands on fetoplacental development with potential impacts on offspring health into adulthood.

2020-07-09 | GSE154026 | GEO

Fetal brain elicits sexually conflicting transcriptional response to the deficiency of uterine Forkhead Box A2 (Foxa2) in mice

Project description:Fetal brain elicits sexually conflicting transcriptional response to the deficiency of uterine Forkhead Box A2 (Foxa2) in mice

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Determination of the Forkhead box A2 (FOXA2) Cistrome in the Human Endometrium

Project description:Uterine glands are central to endometrial function and fertility, however the mechanisms regulating their development and function are not well understood. The pioneer forkhead box A2 (FOXA2) transcription factor is distinctively expressed in the glands of the endometrium in both the human and mouse uterus. Studies in mice established that FOXA2 is a critical regulator of gland development in the neonatal uterus as well as differentiated gland function in the adult uterus. An integrative approach was used here to define the FOXA2 cistrome in the human endometrium. Genome-wide mapping of FOXA2 binding sites by chromatin immunoprecipitation sequencing (ChIP-Seq) was performed on proliferative (P) and mid-secretory (MS) phase endometrium and combined with the transcriptome determined by RNA sequencing (RNA-Seq). Distinctive binding of FOXA2 was observed between the P and MS endometrium, and FOXA2 binding intervals were enriched for different transcription factor binding motifs between the phases of endometrium. Pathway analysis revealed different biological processes regulated by FOXA2 bound genes in the P and MS endometrium. Thus, FOXA2 is proposed to regulate gene expression in concert with other transcription factors to influence gland function in a cycle phase-dependent manner. Further analysis identified potential FOXA2 regulated genes that influence endometrial growth, uterine receptivity, and stromal cell decidualization. This analysis of the FOXA2 cistrome provides a foundation essential to understanding fundamental aspects of uterine gland development, differentiation, function, and disease.

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Determination of the Forkhead box A2 (FOXA2) Cistrome in the Human Endometrium [ChIP-seq]

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