Dataset Information

TFEB controls syncytiotrophoblast formation and estrogen production in placenta

ABSTRACT: TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, is a renowned global modulator of cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying the described phenotype has yet to be elucidated. By integrating multi-omics approaches with functional assays, we uncover an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Here, we showed that syncytiotrophoblast formation is marked by TFEB nuclear translocation and its association with the promoters of crucial placental genes, including fusogenic proteins (Syncytin-1 and Syncythin-2) and enzymes involved in the steroidogenic pathway, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17β-Estradiol (E2). Conversely, the depletion of TFEB negatively impacts both the syncytial fusion and the endocrine properties of the syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placenta hormones and E2 production. Notably, the restoration of TFEB expression resets the syncytiotrophoblast identity. Finally, we identified reduced expression levels of TFEB and its target CYP19A1 in the placenta of pre-eclampsia women, suggesting that dysregulation of the TFEB-CYP19A1 axis might underlie the impairment of placental steroidogenesis described in pre-eclampsia. Our findings elect TFEB as a central controller of the metabolic properties of the placenta by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260620 | GEO | 2024/09/05

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Purpose: Syncytiotrophoblast (STB) is a multi-nucleated, terminally differentiated syncytium that covers the surface of the villous placenta and forms the major interface with maternal blood. It releases placental hormones and plays a primary role in exchange of gases, nutrients and waste products. Alterations in STB development and turnover have been implicated in placental diseases, including preeclampsia (PE). In vitro cell models are badly needed to study STB development and physiology due to inaccessibility to placental tissues during gestation. To establish in vitro STB model system, we generate STB and its mononucleated precursors from human embryonic stem cells (hESC) and profile for RNA content by RNAseq. Methods: H1 Human ESC (WA01) were treated with BMP4, the ALK4/5/7 inhibitor (A83-01), and the FGF2 signaling inhibitor (PD173074) (BAP) to direct them to the trophoblast lineage and provided both STB and extravillous trophoblast. Syncytial areas emerged at day 8 BAP treatment ranged in diameter from ~40 Âµm to > 100 Âµm. The intact syncytial areas were isolated by sieving successively through 70 Î¼m and 40 Î¼m mesh cell strainers. The captured cells are recovered by inverting the strainer and rinsing with culture medium to separate large (>70 Î¼m) and middle size cell sheets (40-70 Î¼m). The fraction that passes through both sieves represents cells of smallest diameter (< 40 Î¼m), presumably cytotrophoblast. Total 12 RNA samples from triplicate three size-fractioned BAP treated and three untreated hESC cultured in a FGF2 supplemented medium in parallel were analyzed. Results: The larger > 70 Î¼m areas stained positively for STB markers while ultrastructural analysis clearly revealed multi-nuclear cells with an extensive cytoplasm containing many prominent secretion granules. The larger STB areas also had a larger DNA content that > 70 Î¼m fraction contained 37 times more nuclear content and 40-70 Âµm fraction did 16 times more. Compared to the < 40 Î¼m cell fraction, these larger cells over-expressed a full repertoire of genes characteristic of STB, e.g. CGA, CGB, PGF, ERVW1, GCM1. The smallest cell fraction had a DNA content consistent with mononuclear diploid cells, contained few secretory granules, and were only weakly positive for STB markers. Conclusion: The data are consistent with the > 70 Î¼m cells being mature STB, while the intermediate fraction may represent a precursor population. Human ESC directed along the trophoblast lineage by BAP treatment offers a useful model for following STB formation in vitro and suggest that this protocol may have utility in studying the basis of certain placental diseases, especially preeclampsia, where placental tissue isolated at term or after pregnancy terminations can only offer limited information. Three size fraction mRNA profiles of syncytial areas emerged at day 8 BAP treatment of hESC were generated by deep sequencing along with untreated hESC, in triplicate, using Illumina HiSeq 2500.

Dataset Information

TFEB controls syncytiotrophoblast formation and estrogen production in placenta

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets