Membrane tension regulated mechanotransduction drives fate transitions in embryonic stem cells
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ABSTRACT:
PROVIDER: PRJNA668927 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12817212_1.fastq.gz | Fastqsanger.gz | |||
| SRR12817212_2.fastq.gz | Fastqsanger.gz | |||
| SRR12817213_1.fastq.gz | Fastqsanger.gz | |||
| SRR12817213_2.fastq.gz | Fastqsanger.gz | |||
| SRR12817214_1.fastq.gz | Fastqsanger.gz |
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Project description:Changes in cell shape and mechanics frequently accompany cell fate transitions. Yet how cellular mechanics affects the regulatory pathways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics and fate, we used embryonic stem (ES) cells, which spread as they undergo early differentiation. We found that this spreading is regulated by a β-catenin mediated decrease in RhoA activity and subsequent decrease in the plasma membrane tension. Strikingly, preventing the membrane tension decrease resulted in early differentiation defects in ES cells and gastruloids. We further find that the decrease in membrane tension facilitates endocytosis of FGF signaling components, which activates ERK signaling and directs exit from the ES cell state. The early differentiation defects we observed can be rescued by increasing Rab5afacilitated endocytosis. Thus, we show that a mechanically-triggered increase in endocytosis regulates early differentiation. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling, and therefore cell fate.
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Project description:Endothelial cell (EC) attachment to the matrix and adjacent cells generates a mechanical environment that maintains a restrictive barrier against the uncontrolled influx of circulating protein and immune cells. Mechanisms that mediate the transition from restrictive to leaky endothelium, a hallmark of tissue injury exemplified by acute lung injury (ALI), remain elusive. Here, we show that FAK sensing and transmission of mechanical tension to the EC nucleus governs cell fate. In FAK-deleted EC, increased EC tension activated DNMT3a, which induced methylation of the KLF2 promoter leading to impaired synthesis of KLF2 and restrictive EC transcriptome, including S1PR1. FAK suppressed DNMT3a activity by restricting the tyrosine phosphorylation of nuclear envelope protein, emerin at Y74/Y95, and its localization in a nuclear cap. Inhibiting emerin phosphorylation or DNMT3a activity in damaged lungs enabled KLF2 transcription of S1PR1, rescuing the restrictive EC phenotype. Our works reveal a paradigm whereby FAK sensing of tension transmission to the nucleus maintains restrictive EC transcriptome and lung homeostasis.
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Project description:Hypoxia augments human embryonic stem cell self-renewal via hypoxia-inducible factor 2M-NM-1 (HIF2M-NM-1) activated OCT4 (POU5F1) transcription. Hypoxia also increases the efficiency of reprogramming differentiated cells to a pluripotent-like state. Combined, these findings suggest that low oxygen (O2) tension would impair the purposeful differentiation of pluripotent stem cells. Here, we show that low O2 tension and HIF activity instead promotes appropriate hESC differentiation. Through gain and loss of function studies, we implicate O2 tension as a modifier of a key cell fate decision, namely whether neural progenitors differentiate towards neurons or glia. Furthermore, our data show that even transient changes in O2 concentration can affect cell fate through HIF by regulating the activity of MYC, a regulator of LIN28/let-7 that is critical for fate decisions in the neural lineage. We also identify key small molecules that can take advantage of this pathway to quickly and efficiently promote the development of mature cell types. We used microarrays to detail the global gene expression of human neural progenitor cells (NPC) cultured in physiological (2%) oxygen tension. By comparing NPCs with activated Hypoxia inducible factor (HIF) activity (DFX treatment) and NPCs with diminished HIF activity (HIF1M-NM-2 knockdown), we identified genes that are important for NPC fate decision under physiological oxygen concentration. We also used microarrays to obtain a global gene expression profiling during embryoid bodies formation using ES cells with diminished HIF activity. In HIF activation experiments, two ES lines and one iPS line-derived NPC were used, with or without DFX treatment for 5 days. In HIF1M-NM-2 knockdown experiments, NPCs were derived from either shHIF1M-NM-2 or control ES lines. In embryoid body formation experiments, day0 (ES stage) and day6 EBs were generated from either shHIF1M-NM-2 or control ES lines in 2% oxygen.
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