Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tension sensing by FAK governs nuclear mechanotransduction, trancriptome and fate endothelial transcriptome and fate

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE212037 | GEO | 2022/08/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

FAK is required for suppressing aberrant nuclear mechanotransduction and DNA methylation to prevent vascular injury

Project description:Mechanical forces generated through adhesive interaction of endothelial cells (EC) influence nuclear envelope and thereby gene transcription. Alteration in EC mechanical forces may trigger aberrant gene transcription leading to lethal vascular diseases including acute lung injury (ALI). The intrinsic pathways that instruct EC nuclear-mechanotransduction and thereby maintains vascular homeostasis remain elusive. We have identified focal adhesion kinase (FAK)-mediated mechanotransduction at the nuclear envelope in instructing transcription of EC-barrier protective genes. We show that loss of EC-FAK increases intracellular tension, which in turn activates nuclear envelop protein emerin, and DNA methyltransferase 3a (DNMT3a). Methylation of transcription factor KLF2 promoter by DNMT3a impaired KLF2 synthesis and transcription of the crucial barrier-maintaining gene, S1PR1. Restoring KLF2 or S1PR1 expression or impairing emerin or DNMT3a activity rescued vascular homeostasis in lungs with FAK-deficient or WT-damaged endothelium. Thus, FAK protects against tension-induced aberrant DNA methylation in EC and is a promising target to prevent ALI.

2022-07-11 | GSE207789 | GEO

Krüppel-like factor 2 in VCAM1+ endothelial cells is a critical regulator of vascular inflammation

Project description:Endothelial cells (ECs) act as an internal barrier to the vessel wall, hindering the development of inflammation, and only when activated will promote the development of vascular inflammation. However, the heterogeneity of the aortic ECs in the setting of vascular inflammation have not been fully assessed. Here, we defined 4 EC subpopulations, including Cd36+ EC, Notch3+ EC, Vcam1+ EC and Lyve1+ EC. Based on the enrichment analysis, Vcam1+ EC were considered to be a subpopulation of ECs susceptible to activation. After high-fat diet (HFD) intake, decreased expression of Krüppel-like factor 2 (Klf2) occurred only in Vcam1+ EC. Moreover, S1pr1 was validated as a downstream target protein of klf2. Upregulation of Klf2 expression ameliorated vascular ECs inflammation under HFD condition. Our study elucidates the Klf2 in Vcam1+ EC is a critical regulator of vascular inflammation and increases understanding of development and progression of aortic inflammatory disease.

2024-01-01 | GSE214014 | GEO

Programming to S1PR1+ Endothelial Cell Promotes Restoration of Lung Vascular Integrity

Project description:Increased endothelial permeability and failure to repair is the hallmark of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways that activate endothelial cell (EC) regenerative programs and thereby tissue repair. Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Here, we addressed mechanisms of generation of S1PR1+ EC, which may prevent endothelial injury. Studies were made using inducible EC-S1PR1-/- (iEC-S1PR1-/-) mice and S1PR1-GFP reporter mice to trace the generation of S1PR1+ EC. We observed in a mouse model of endotoxemia that S1P generation induced the programming of S1PR1lo to S1PR1+ EC, which comprised 80% of lung EC. The transition of these cells was required for reestablishing the endothelial barrier. We also observed that conditional deletion of S1PR1 in EC increased vascular permeability. RNA-seq analysis of S1PR1+ EC showed enrichment of genes regulating S1P synthesis and transport, sphingosine kinase 1 (SPHK1) and SPNS2, respectively. The activation of transcription factors EGR1 and STAT3 were essential for transcribing SPHK1 and SPNS2, respectively, to increase S1P production that served to amplify S1PR1+ EC transition. Transplantation of S1PR1+ EC into injured lung vasculature restored endothelial integrity. Our findings show that generation of a S1PR1+ EC population activates the endothelial regenerative program mediating vascular endothelial repair, thus raising the possibility of harnessing this pathway to restore vascular homeostasis in inflammatory injury.

2023-01-15 | GSE165000 | GEO

Angiogenic patterning by STEEL, an endothelial-enriched long noncoding RNAAngiogenic patterning by STEEL, an endothelial-enriched long noncoding RNA

Project description:Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell-type specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for STEEL (spliced transcript – endothelial enriched lncRNA) in angiogenic potential, macrovascular/microvascular identity and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear-enriched and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse endothelial cells. Of interest, STEEL upregulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL upregulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces, and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.

2018-02-28 | PXD008581 | Pride

Fibroblast-specific focal adhesion kinase links mechanical force to fibrosis via chemokine-mediated inflammatory pathways

Project description:Hypertrophic scar (HTS) formation is characterized by exuberant fibroproliferation for reasons that remain poorly understood1. One important but often overlooked component of wound repair is mechanical force, which regulates reciprocal cell-matrix interactions through focal adhesion components including focal adhesion kinase (FAK)1,2. Here we report that FAK is activated following cutaneous injury and that this activation is potentiated by mechanical loading. Transgenic mice lacking fibroblast-specific FAK exhibit significantly less fibrosis in a preclinical model of HTS formation. Inflammatory pathways involving monocyte chemoattractant protein-1 (MCP-1), a chemokine highly implicated in human skin fibrosis3, are triggered following FAK activation, mechanistically linking physical force to fibrosis. Further, small molecule inhibition of FAK effectively abrogates fibroproliferative mechanisms in human cells and significantly reduces scar formation in vivo. Collectively, these findings establish a molecular basis for HTS formation based on the mechanical activation of fibroblast-specific FAK and demonstrate the therapeutic potential of targeted mechanomodulatory strategies. Wildtype murine tissue was harvested at either day 6 or 14 post-injury following 48 hours or 10 days of mechanical loading, respectively (n=4 mice per group per time point). Murine RNA was isolated, labeled, and hybridized to the GeneChip microarray according to the manufacturer’s protocols (Affymetrix, Santa Clara, CA, USA). Each gene in the microarray was represented by 20 oligonucleotide pairs, with each pair consisting of an oligonucleotide perfectly matched to the cDNA sequence, and a second oligonucleotide containing a single base mismatch. Raw microarray data (sample intensity files) were processed using GeneSpring GX 11.0 (Agilent Technologies Inc., Santa Clara, CA, USA).

2011-01-14 | E-GEOD-26390 | biostudies-arrayexpress

Hobit and Blimp1 instruct a universal transcriptional program of tissue-residency in lymphocytes

Project description:Tissue-resident memory T cells (Trm) permanently localize to portals of pathogen entry, where they provide immediate protection against re-infection. To enforce tissue retention, Trm upregulate CD69 and downregulate molecules associated with tissue egress including CCR7 and S1PR1. Although suppression of the transcription factor KLF2 in Trm prevents S1PR1-driven migration, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically upregulated in Trm and together with related Blimp1, mediates the development of Trm in skin, gut, liver and kidney. Importantly, the Hobit/Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes including NKT cells and liver-resident NK cells, all of which share a common transcriptional program that includes repression of Ccr7, S1pr1, and Klf2. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.

2016-04-25 | GSE79339 | GEO

Low endothelial cell FAK expression reduces pancreatic ductal adenocarcinoma liver metastasis after gemcitabine treatment

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a high level of liver metastasis. Despite substantial advances, resistance to therapy, including gemcitabine, is still a major obstacle to improved progression free survival. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy induced angiocrine factors and chemosensitivity in malignant cells. However, the effect of EC-FAK regulated angiocrine signalling in chemosensitivity of metastatic PDAC remains unexplored. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC reduces liver metastasis and improves survival rates in gemcitabine treated, but not untreated, mice, without affecting primary tumour growth, tumour vascularization, blood vessel leakage or early metastatic events. Phosphoproteomics analysis show a downregulation of the MAPK/ RAF/ PAK signalling pathways in gemcitabine treated FAK-depleted ECs compared to gemcitabine treated WT ECs. Moreover, low levels of EC-FAK correlate with increased survival and reduced relapse in gemcitabine treated human PDAC patients, supporting the clinical relevance of our findings. Altogether, we have identified a new role of EC-FAK regulating PDAC liver metastasis upon gemcitabine treatment that impacts on survival.

2023-03-10 | PXD021542 | Pride

Genetic reporter for live tracing fluid flow forces during cell fate segregation in mouse blastocyst development

Project description:We used a robut low input cell and high throughput in-situ ChIP method to emphasize regulation mechanism among E3.5 klf2, E3.5 klf4 and E12.5 EC klf2.

2023-07-31 | GSE197167 | GEO

Fibroblast-specific focal adhesion kinase links mechanical force to fibrosis via chemokine-mediated inflammatory pathways

2011-01-14 | GSE26390 | GEO

Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

Project description:Impact of static mechanical tension on global gene expressison in dendritic cell culture

2021-11-14 | GSE162061 | GEO