Potential role of FoxO3a in the regulation of trophoblast development and pregnancy complications

Chen, Hao; Tang, Xin; Han, Ting‐Li; Zhu, Jing; Zhou, Wei; Baker, Philip N.; Chang, Chen; Zhang, Hua

doi:10.1111/jcmm.16499

Cited by 9 publications

(8 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Namely, multiple families bore motifs for key factors involved in the maintenance of the stem cell state, such as ELF5, GATA3, TFAP2C, TP63 and TEAD4 (Figure 2A; Supplementary Figure 2A). Additional transcription factors with known roles in placental development and/or physiology included JUN/FOS (He et al, 2019; Kubota et al, 2015), PPARG/RXRA (Kadam et al, 2015), and FOXO3 (Chen et al, 2021). To validate the binding of some of these transcription factors to hTSC-active TEs, we performed CUT&Tag or CUT&RUN (Skene and Henikoff, 2017) for JUN, JUND, GATA3, TEAD4 and TFAP2C (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

“…Namely, multiple families bore motifs for key factors involved in the maintenance of the stem cell state, such as ELF5, GATA3, TFAP2C, TP63 and TEAD4 (Figure 2A; Supplementary Figure 2A). Additional transcription factors with known roles in placental development and/or physiology included JUN/FOS 27,28 , PPARG/RXRA 29 , and FOXO3 30 . Most of these motifs were also present in elements negative for H3K27ac (Supplementary Figure 2B), suggesting that there are additional genetic or epigenetic determinants of their activity, similar to what we had observed in mouse TSCs 18 .…”

Section: Htsc-active Ervs Bind Key Placenta-associated Transcription ...mentioning

confidence: 99%

See 1 more Smart Citation

Regulation of human trophoblast gene expression by endogenous retroviruses

Frost

Amante

Okae

et al. 2022

Preprint

View full text Add to dashboard Cite

The placenta is a fast-evolving organ with large morphological and histological differences across eutherians, but the genetic changes driving placental evolution have not been fully elucidated. Transposable elements, through their capacity to quickly generate genetic variation and affect host gene regulation, may have helped to define species-specific trophoblast gene expression programmes. Here, we assessed the contribution of transposable elements to human trophoblast gene expression as enhancers or promoters. Using epigenomic data from primary human trophoblast and trophoblast stem cell lines, we identified multiple endogenous retrovirus families with regulatory potential that lie close to genes with preferential expression in trophoblast. These largely primate-specific elements are associated with inter-species gene expression differences, and are bound by transcription factors with key roles in placental development. Using genetic editing we demonstrated that several elements act as transcriptional enhancers of important placental genes, such as CSF1R and PSG5. We also identified an LTR10A element that regulates ENG expression, affecting secretion of soluble ENG, with potential implications for preeclampsia. Our data show that transposons have made important contributions to human trophoblast gene regulation, and suggest that their activity may affect pregnancy outcomes.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Namely, multiple families bore motifs for key factors involved in the maintenance of the stem cell state, such as ELF5, GATA3, TFAP2C, TP63 and TEAD4 (Figure 2A; Supplementary Figure 2A). Additional transcription factors with known roles in placental development and/or physiology included JUN/FOS 27,28 , PPARG/RXRA 29 , and FOXO3 30 . Most of these motifs were also present in elements negative for H3K27ac (Supplementary Figure 2B), suggesting that there are additional genetic or epigenetic determinants of their activity, similar to what we had observed in mouse TSCs 18 .…”

Section: Htsc-active Ervs Bind Key Placenta-associated Transcription ...mentioning

confidence: 99%

Regulation of human trophoblast gene expression by endogenous retroviruses

Frost

Amante

Okae

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Recently, several researchers reported that tryptophan (one of the three aromatic amino acids) had been involved in migration and invasion via cyclooxygenase-2 (COX-2, also named PTGS2) and matrix metallopeptidase 9 (MMP9) (Gu et al 2021 ; Liu et al 2020 ). Our previous RNA-seq study consistently demonstrated that COX-2 and MMP9 were decreased after FoxO3a depletion (Chen et al 2021 ), and the expression of these two genes is negatively correlated with all three aromatic amino acids acid concentrations under FoxO3a knockdown condition (Fig. 6 B).…”

Section: Discussionmentioning

confidence: 99%

A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming

Chen

Wang

Chen

et al. 2022

Mol Med

Self Cite

View full text Add to dashboard Cite

Background The forkhead box O3a protein (FoxO3a) has been reported to be involved in the migration and invasion of trophoblast, but its underlying mechanisms unknown. In this study, we aim to explore the transcriptional and metabolic regulations of FoxO3a on the migration and invasion of early placental development. Methods Lentiviral vectors were used to knock down the expression of FoxO3a of the HTR8/SVneo cells. Western blot, matrigel invasion assay, wound healing assay, seahorse, gas-chromatography-mass spectrometry (GC–MS) based metabolomics, fluxomics, and RNA-seq transcriptomics were performed. Results We found that FoxO3a depletion restrained the migration and invasion of HTR8/SVneo cells. Metabolomics, fluxomics, and seahorse demonstrated that FoxO3a knockdown resulted in a switch from aerobic to anaerobic respiration and increased utilization of aromatic amino acids and long-chain fatty acids from extracellular nutrients. Furthermore, our RNA-seq also demonstrated that the expression of COX-2 and MMP9 decreased after FoxO3a knockdown, and these two genes were closely associated with the migration/invasion progress of trophoblast cells. Conclusions Our results suggested novel biological roles of FoxO3a in early placental development. FoxO3a exerts an essential effect on trophoblast migration and invasion owing to the regulations of COX2, MMP9, aromatic amino acids, energy metabolism, and oxidative stress.

show abstract

“…Here, we found that DNA methylation in the enhancer regions of SPATS2L resulted in decreased protein expression in chorionic villi. The human extravillous trophoblast cell line HTR8/SVneo is widely used as a model for first trimester extravillous trophoblasts invasion and migration 28 – 30 . Our functional study using this cell line revealed that SPATS2L is involved in its migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

Characteristic DNA methylation profiles of chorionic villi in recurrent miscarriage

Matsumoto

Shinjo

Mase

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Dysregulation of transcriptional programs that are tightly regulated by DNA methylation during placental and fetal development at different gestational stages, may cause recurrent miscarriage. Here, we examined genome-wide DNA methylation in chorionic villi and decidual tissues from patients suffering RM and from healthy women who had undergone artificial abortion (n = 5 each). We found that 13,426 and 5816 CpG sites were differentially methylated in chorionic villi and decidua, respectively. DNA methylation profiles of chorionic villi, but not decidua, in RM patients was clearly distinct from AA controls. Among the differentially methylated genes, the enhancer region of SPATS2L was significantly more highly methylated in RM patients (n = 19) than AA controls (n = 19; mean methylation level, 52.0%-vs.-28.9%, P < 0.001), resulting in reduced expression of SPATS2L protein in the former. Functionally, depletion of SPATS2L in extravillous trophoblast cells decreased their invasion and migration abilities. Our data indicate that particularly the chorionic villi in RM patients exhibit distinct DNA methylation profiles compared with normal pregnancies and that this changed DNA methylation status may impede the progression of embryo development via the altered expression of genes such as SPATS2L in the villi.

show abstract

Potential role of FoxO3a in the regulation of trophoblast development and pregnancy complications

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 9 publications

References 41 publications

Regulation of human trophoblast gene expression by endogenous retroviruses

Regulation of human trophoblast gene expression by endogenous retroviruses

A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming

Characteristic DNA methylation profiles of chorionic villi in recurrent miscarriage

Contact Info

Product

Resources

About