TFEB controls syncytiotrophoblast formation and estrogen production in placenta [ChIP-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE260617 | GEO | 2024/09/05
REPOSITORIES: GEO
Similar Datasets
Project description: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.
2024-09-05 | GSE260620 | GEO
Project description:TFEB controls syncytiotrophoblast formation and estrogen production in placenta
| PRJNA1082361 | ENA
Project description:During human development, a subset of differentiating fetal cells form a temporary organ, the placenta, which invades the uterine wall to support nutrient, oxygen, and waste exchange between the mother and fetus until birth. Most of the human placenta is formed by a syncytial villous structure which arises via cell-cell fusion of underlying fetal trophoblast stem cells. Genetic and functional studies have characterized the membrane protein fusogens, Syncytin-1 and Syncytin-2, that are both necessary and sufficient for human trophoblast cell-cell fusion. However, identification and characterization of upstream transcriptional regulators regulating their expression has been limited. Here, using CRISPR knockout in an in vitro cellular model of syncytiotrophoblast development (BeWo cells), we find that the transcription factor TFEB, mainly known as a regulator of autophagy and lysosomal biogenesis, is required for cell-cell fusion of syncytiotrophoblasts. TFEB translocates to the nucleus, exhibits increased chromatin interactions, and directly binds the Syncytin-1 and Syncytin-2 promoters to control their expression during differentiation. While TFEB appears to play an important role in syncytiotrophoblast differentiation, ablation of TFEB largely does not affect lysosomal gene expression or lysosomal biogenesis in differentiating BeWo cells, suggesting that TFEB plays an alternative role in placental cells.
2024-12-18 | GSE284600 | GEO
Project description:TFEB controls syncytiotrophoblast formation and estrogen production in placenta [ChIP-Seq]
| PRJNA1082355 | ENA
Project description:In order to identify the effects of transcription factor EB (TFEB) overexpression on the liver transcriptome, we performed Affymetrix GeneChip hybridization experiments on injected mice overexpressing TFEB specifically in the liver. For the analysis of the injected mice overexpressing TFEB, total RNA was extracted from the liver of three mice. RNA extracted from the liver of 3 not-injected mice was used as a control.
2013-04-20 | E-GEOD-35015 | biostudies-arrayexpress
Project description:Our studies in Salmonella Typhimurium (S. Typhimurium)-infected cells indicate that TFEB has a non-transcriptional, cytosolic function in addition to its well-characterized role as a transcription factor in regulating autophagy and lysosome biogenesis. An unbiased proteomics approach revealed that TFEB interacts with several mitochondrial proteins, which is lost when infected with S. Typhimurium. Microscopical and biochemical examinations further confirmed a novel localization of TFEB in mitochondria. We have also identified a TOMM20 binding motif within the protein sequence of TFEB which, facilitates the mitochondrial translocation in a mTOR-dependent manner. Our results further demonstrate that TFEB and the mitochondrial protease LonP1 co-regulate the assembly of complex I and its function. Moreover, during S. Typhimurium infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines.
2024-05-21 | PXD013758 | Pride
Project description:Total RNA samples from three biological replicates in which TFEB was transiently overexpressed in HeLa cells by transfection using a pcDNA3 vector. As negative control, we used total RNA samples from HeLa cells transfected with an empty pcDNA3 vector. TFEB transfection
2010-04-09 | E-GEOD-16267 | biostudies-arrayexpress
Project description:The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. We identify a distinct nuclear interactome of TFEB, with USP7 emerging as a key post-translational modulator of TFEB. Genetic depletion and inhibition of USP7 reveal its critical role in preserving TFEB stability within both nuclear and cytoplasmic compartments. Specifically, USP7 is identified as the deubiquitinase responsible for removing the K48-linked polyubiquitination signal from TFEB at lysine residues K116, K264, and K274, thereby preventing its proteasomal degradation. Functional assays demonstrate the involvement of USP7 in preserving TFEB-mediated transcriptional responses to nutrient deprivation, while also modulating autophagy flux and lysosome biogenesis. As USP7 is a deubiquitinase that protects TFEB from proteasomal degradation, these findings provide the foundation for therapeutic targeting of the USP7-TFEB axis in conditions characterized by TFEB dysregulation and metabolic abnormalities, particularly in certain cancers.
2024-09-17 | PXD055937 | Pride
Project description:Trophoblast fusion is a central step in placental physiology. This mechanisms can be studied in the BeWO cell model that fuse following forskolin treatment that activates the c-AMP cascade.
2020-12-16 | E-MTAB-9832 | biostudies-arrayexpress
Project description:Expression data from Ppara (peroxisome proliferator activated receptor alpha) KO mice injected with TFEB specifically in liver. In order to identify the effects of TFEB overexpression together with Ppara absence on the liver transcriptome, we performed Affymetrix Gene-Chip hybridization experiments for the injected mice For the analysis on the injected Ppara-KO mice overexpressing TFEB, total RNA was extracted from the liver of three mice; RNA extracted from the liver of not-injected mice was used as control.
2013-04-20 | E-GEOD-41140 | biostudies-arrayexpress