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Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE129721 | GEO | 2020/05/24

REPOSITORIES: GEO

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Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers.

Project description:Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively. We demonstrate that YAP is preferentially co-localized with super-enhancer (SE) markers such as Nanog, Sox2, Oct4 and H3K27ac in ESCs. The hyper-activation of nuclear YAP in Mst KO ESCs facilitates the binding of Nanog, Sox2 and Oct4 as well as H3K27ac modification at the loci where YAP binds. Moreover, Mst depletion results in novel SE formation and enhanced liquid-liquid phase-separated Med1 condensates on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Our study reveals a novel mechanism on how Hippo-YAP signaling pathway dictates ESC lineage differentiation.

| S-EPMC7367178 | biostudies-literature

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [RNA-seq]

Project description:Hippo-YAP signaling pathway is a highly conserved pathway during evolution. It involves in a broad spectrum of physiological and pathological procedure. It also functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. Our previous research revealed that knockout of Mst1 and Mst2, the key components of Hippo signaling in mouse embryonic stem cells (ESCs), led ESCs preferentially differentiate into ectoderm lineage, and the differentiation to mesoderm and endoderm lineage was disturbed. To uncover the underlying regulatory mechanisms, we performed ChIP-seq experiments with antibodies against Yap, master transcription factors and some characterized histone modification markers. Combined with RNA-seq assays of wild type and Mst KO ESCs and day 4 embryoid bodies (EBs), we found that YAP is preferentially enriched at Nanog, Sox2, Oct4 and H3K27Ac co-marked super-enhancers (SEs) in ESCs. The upregulation of YAP in Mst KO ESCs resulted in the formation of new super-enhancers on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Hence, our study revealed a super-enhancer related ESC lineage differentiation mechanism which can be shaped by Hippo-YAP signaling.

2020-05-24 | GSE144579 | GEO

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [ChIP-seq 2]

2020-05-24 | GSE144578 | GEO

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [ChIP-seq 1]

2020-05-24 | GSE144577 | GEO

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers

Project description:Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers

| PRJNA532585 | ENA

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [RNA-seq]

Project description:Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [RNA-seq]

| PRJNA604041 | ENA

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [ChIP-seq 2]

Project description:Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [ChIP-seq 2]

| PRJNA604042 | ENA

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [ChIP-seq 1]

Project description:Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cell through super-enhancers [ChIP-seq 1]

| PRJNA604043 | ENA

Hippo/Yap signaling controls epithelial progenitor cell proliferation and differentiation in the embryonic and adult lung.

Project description:The Hippo/Yap pathway is a well-conserved signaling cascade that regulates cell proliferation and differentiation to control organ size and stem/progenitor cell behavior. Following airway injury, Yap was dynamically regulated in regenerating airway epithelial cells. To determine the role of Hippo signaling in the lung, the mammalian Hippo kinases, Mst1 and Mst2, were deleted in epithelial cells of the embryonic and mature mouse lung. Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation. The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated following embryonic Mst1/2 deletion. Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation. Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion, consistent with canonical Hippo/Yap signaling. YAP potentiated cell proliferation and inhibited differentiation of human bronchial epithelial cells in vitro. Loss of Mst1/2 and expression of YAP regulated transcriptional targets controlling cell proliferation and differentiation, including Ajuba LIM protein. Ajuba was required for the effects of YAP on cell proliferation in vitro. Hippo/Yap signaling regulates Ajuba and controls proliferation and differentiation of lung epithelial progenitor cells.

| S-EPMC4400400 | biostudies-literature

Lysophosphatidic Acid Accelerates Bovine In Vitro-Produced Blastocyst Formation through the Hippo/YAP Pathway.

Project description:The segregation of trophectoderm (TE) and inner cell mass in early embryos is driven primarily by the transcription factor CDX2. The signals that trigger CDX2 activation are, however, less clear. In mouse embryos, the Hippo-YAP signaling pathway is important for the activation of CDX2 expression; it is less clear whether this relationship is conserved in other mammals. Lysophosphatidic acid (LPA) has been reported to increase YAP levels by inhibiting its degradation. In this study, we cultured bovine embryos in the presence of LPA and examined changes in gene and protein expression. LPA was found to accelerate the onset of blastocyst formation on days 5 and 6, without changing the TE/inner cell mass ratio. We further observed that the expression of TAZ and TEAD4 was up-regulated, and YAP was overexpressed, in LPA-treated day 6 embryos. However, LPA-induced up-regulation of CDX2 expression was only evident in day 8 embryos. Overall, our data suggest that the Hippo signaling pathway is involved in the initiation of bovine blastocyst formation, but does not affect the cell lineage constitution of blastocysts.

| S-EPMC8198578 | biostudies-literature

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