Trophoblast syncytialization maintains the placenta-heart axis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA953770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24112567_1.fastq.gz | Fastqsanger.gz | |||
| SRR24112567_2.fastq.gz | Fastqsanger.gz | |||
| SRR24112568_1.fastq.gz | Fastqsanger.gz | |||
| SRR24112568_2.fastq.gz | Fastqsanger.gz | |||
| SRR24112569_1.fastq.gz | Fastqsanger.gz |
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Project description:The developmental connection between the placenta and certain embryonic organs, such as the heart, is associated with normal pregnancy and complications, but how the placenta governs embryonic cardiogenesis is poorly understood. Trophoblasts fuse into a multinucleated syncytiotrophoblast (SynT) layer, primarily consisting of a placental materno-fetal interface. We identify that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is essential for trophoblast differentiation and fusion into SynT in human trophoblasts and mouse placentas. Moreover, SynT-derived PIBF1 enables the communication between SynT and adjacent vascular cells to develop the vascular network in the primary placenta and further impacts the early development of the embryonic cardiovascular system in an endocrine manner. Thus, SynT-derived factors and SynT itself in the placenta may play crucial roles in the proper organogenesis of other organs in the embryo.
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Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
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Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
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Project description:Nutrient sensing and adaptation in the placenta are essential for pregnancy viability and proper fetal growth. Our recent research demonstrates that the placenta adapts to nutrient insufficiency through mTOR inhibition-mediated trophoblast differentiation toward syncytiotrophoblasts (STBs), a highly specialized multinucleated trophoblast subtype directing extensive maternal-fetal interactions. However, the underlying mechanism remains elusive. Here, we unravel the indispensable role of the mTORC1 downstream transcriptional factor TFEB in STB formation both in vitro and in vivo. Endogenous TFEB deficiency significantly impaired STB differentiation in trophoblast cells and placenta organoids. Mechanistically, TFEB conferred direct transcriptional regulation of the fusogen ERVFRD-1 in human trophoblasts and thereby profoundly promoted STB formation, independent of its canonical function as a master regulator of the autophagy-lysosomal pathway. In line with the in vitro findings, systemic or trophoblast-specific deletion of Tfeb compromised STB formation and placental vascular construction, leading to severe embryonic lethality. Moreover, TFEB directs the trophoblast syncytialization response driven by mTORC1 signaling. Importantly, TFEB expression positively correlates with the reinforced trophoblast syncytialization in human fetal growth restriction (FGR) placentas exhibiting suppressed mTORC1 activity. Our findings substantiate that the TFEB-fusogen axis ensures proper STB formation during placenta development and under nutrient stress, shedding light on TFEB as a mechanistic link between nutrient-sensing machinery and trophoblast differentiation.
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Project description:Multinucleated syncytiotrophoblasts (STBs), which are in direct contact with maternal blood, constitute the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. However, the genetic and epigenetic regulatory mechanisms governing trophoblast syncytialization remain largely elusive. We delineate that endogenous retroviruses (ERVs), which have been exapted as regulatory sequences for specific functional adaptations in placenta, profoundly rewire transcriptional program of trophoblast syncytialization. Here, we first determined dynamic bivalent ERV-derived enhancers with dual occupancy of H3K9me3 and H3K27ac in human trophoblast stem cells (hTSCs), which emerge as cell specific regulators of gene expression with markedly resolved H3K9me3 during differentiation towards STBs. Of note, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of STB-specific genes. Importantly, depletions of MER50 elements adjacent to several STB genes, including MFSD2A, TNFAIP2 and RAI14, significantly attenuated their expression concomitant to dysregulated syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional program accounting for human trophoblast syncytialization, which sheds light on novel epigenetic regulatory mechanisms underlying placental development.
2023-02-03 | GSE209976 | GEO
Project description:Multinucleated syncytiotrophoblasts (STBs), which are in direct contact with maternal blood, constitute the maternal-fetal interface critical for nutrient allocation, hormone production and immunological modulation during pregnancy. However, the genetic and epigenetic regulatory mechanisms governing trophoblast syncytialization remain largely elusive. We delineate that endogenous retroviruses (ERVs), which have been exapted as regulatory sequences for specific functional adaptations in placenta, profoundly rewire transcriptional program of trophoblast syncytialization. Here, we first determined dynamic bivalent ERV-derived enhancers with dual occupancy of H3K9me3 and H3K27ac in human trophoblast stem cells (hTSCs), which emerge as cell specific regulators of gene expression with markedly resolved H3K9me3 during differentiation towards STBs. Of note, bivalent enhancers derived from the Simiiformes-specific MER50 transposons were linked to a cluster of STB-specific genes. Importantly, depletions of MER50 elements adjacent to several STB genes, including MFSD2A, TNFAIP2 and RAI14, significantly attenuated their expression concomitant to dysregulated syncytium formation. Together, we propose that ERV-derived enhancers, MER50 specifically, fine-tune the transcriptional program accounting for human trophoblast syncytialization, which sheds light on novel epigenetic regulatory mechanisms underlying placental development.
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