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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from pulmonary arterial endothelial cells treated with siRNA control or siGLS in stiff or soft matrix

ABSTRACT: Dysregulation of vascular stiffness and cellular metabolism occur early in pulmonary hypertension (PH). Yet, the mechanisms by which biophysical properties of extracellular matrix relate to metabolic processes and downstream PH phenotypes remain undefined. In cultured endothelial and smooth muscle cells and confirmed in PH-diseased human samples, we found that ECM stiffening activates the mechanosensitive factors YAP/TAZ to increase glycolysis and induce glutaminase (GLS) expression and glutaminolysis. Glutaminolysis replenishes aspartate for anabolic biosynthesis, thus sustaining proliferation and migration within stiff ECM. In vitro GLS inhibition blocks aspartate production, consequently reprogramming entire cellular proliferative pathways, while aspartate restores proliferation. In a rat model in vivo, GLS inhibition prevents hemodynamic and histologic manifestations of PH. Thus, mechanical ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis â a paradigm that advances our understanding of the connections of mechanical stimuli with dysregulated vascular metabolism and identifies new metabolic drug targets in PH. We used microarrays to decipher the global program of gene expression involved in response to matrix stiffening and determined the implication of glutaminolysis (GLS) in these process PAECs were transfected with an siRNA control (siNC) or a siRNA against GLS (siGLS) and cultivated on soft hydrogel (1kPa) or stiff hydrogel (50kPa). After 48h of transfection cells were lysate and RNA extract for hybridization on Affymetrix microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas BERTERO

PROVIDER: E-GEOD-75793 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from pulmonary arterial endothelial cells treated with siRNA control or siGLS in stiff or soft matrix

Project description:Dysregulation of vascular stiffness and cellular metabolism occur early in pulmonary hypertension (PH). Yet, the mechanisms by which biophysical properties of extracellular matrix relate to metabolic processes and downstream PH phenotypes remain undefined. In cultured endothelial and smooth muscle cells and confirmed in PH-diseased human samples, we found that ECM stiffening activates the mechanosensitive factors YAP/TAZ to increase glycolysis and induce glutaminase (GLS) expression and glutaminolysis. Glutaminolysis replenishes aspartate for anabolic biosynthesis, thus sustaining proliferation and migration within stiff ECM. In vitro GLS inhibition blocks aspartate production, consequently reprogramming entire cellular proliferative pathways, while aspartate restores proliferation. In a rat model in vivo, GLS inhibition prevents hemodynamic and histologic manifestations of PH. Thus, mechanical ECM stiffening sustains vascular cell growth and migration through YAP/TAZ-dependent glutaminolysis – a paradigm that advances our understanding of the connections of mechanical stimuli with dysregulated vascular metabolism and identifies new metabolic drug targets in PH. We used microarrays to decipher the global program of gene expression involved in response to matrix stiffening and determined the implication of glutaminolysis (GLS) in these process

2016-09-01 | GSE75793 | GEO

Mining the stiffness-sensitive transcriptome in human vascular smooth muscle cells identifies long non-coding RNA stiffness regulators

Project description:Vascular extracellular matrix (ECM) stiffening is a risk factor for aortic and coronary artery disease. How matrix stiffening regulates the transcriptome profile of human aortic (Ao) and coronary (Co) vascular smooth muscle cells (VSMCs) is not well understood. Furthermore, the role of long non-coding RNAs (lncRNAs) in the cellular response to stiffening has never been explored. This study characterizes the stiffness-sensitive transcriptome of human Ao and Co VSMCs and identify potentially key lncRNA regulators of stiffness-dependent VSMC functions. Ao and Co VSMCs were cultured on hydrogel substrates mimicking physiologic and pathologic ECM stiffness. Total RNA-seq was performed to compare the stiffness-sensitive transcriptome profiles of Ao and Co VSMCs.

2017-12-01 | GSE100081 | GEO

A YAP/TAZ-TEAD signaling module links endothelial nutrient acquisition to angiogenic growth

Project description:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are dictated by YAP/TAZ-TEAD – a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2, and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fueling nutrient mTORC1 signaling. By orchestrating the transcription of a repertoire of cell-surface transporters, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 pathway activation. Dissociating mTORC1 from these nutrient inputs – elicited by the loss of Rag GTPases – inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. These findings define a pivotal role for YAP/TAZ-TEAD in steering endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.

2022-05-08 | PXD026872 | Pride

A MYC-driven change in mitochondrial dynamics limits stem cell properties of mammary epithelial cells (ChIP-seq)

Project description:In several developmental lineages, an increase in expression of the MYC proto-oncogene drives the transition from quiescent stem cells to transit amplifying cells. The mechanism by which MYC restricts self-renewal of adult stem cells is unknown. Here, we show that MYC activates a stereotypic transcriptional program of genes involved in protein translation and mitochondrial biogenesis in mammary epithelial cells and indirectly inhibits the YAP/TAZ co-activators that are essential for mammary stem cell self-renewal. We identify a phospholipase of the mitochondrial outer membrane, PLD6, as the mediator of MYC activity. PLD6 mediates a change in the mitochondrial fusion/fission balance that promotes nuclear export of YAP/TAZ in a LATS- and RHO-independent manner. Mouse models and human pathological data confirm that MYC suppresses YAP/TAZ activity in mammary tumors. PLD6 is also required for glutaminolysis, arguing that MYC-dependent changes in mitochondrial dynamics balance cellular energy metabolism with the self-renewal potential of adult stem cells. ChIP-Seq experiments for MYC-HA (HA-IP) performed in IMEC primary breast epithelial cells. Input-samples were sequenced as controlls.

2015-10-28 | E-GEOD-66252 | biostudies-arrayexpress

YAP-TEAD multiphasic activation regulates pluripotent stem cell mechanics to drive cardiac specification and contractility in pathological heart.

Project description:YAP transcriptional regulator controls cell mechanics by activating genes involved in cell-matrix interaction following extracellular matrix (ECM) remodelling and stiffening. YAP is needed for cardiogenesis in mouse but is repressed in adult cardiomyocytes. The protein is reactivated following ischemic insults, although the timing and mechanisms underlying YAP depletion during heart development and the reason for its reactivation are unclear. Here, we combine pluripotent stem cell (PSC) cardiac differentiation, mouse embryo development and human heart tissue analysis to demonstrate that the fine-tuning of cell mechanics, as controlled by YAP multiphasic activation through TEAD transcription, is crucial for mesoderm commitment and cardiac progenitor specification. Finally, by adopting induced PSC models of dilated cardiomyopathy, we prove that YAP-TEAD reactivation in diseased cardiomyocytes empowers calcium handling apparatus and increases cell contractility. Given YAP prompt activation following myocardial infarction, we unveil a novel role for mechanosensing in connecting ECM remodelling to cardiomyocyte function in pathological heart.

2020-10-30 | E-MTAB-7619 | biostudies-arrayexpress

YAP-TEAD multiphasic activation regulates pluripotent stem cell mechanics to drive cardiac specification and contractility in pathological heart.

2020-10-30 | E-MTAB-7620 | biostudies-arrayexpress

Proteomic analysis glomeruli of PAN-treated rats

Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP hyper-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.

2017-05-02 | PXD003864 | Pride

Response of podocytes to PAN - YAP-mediated mechanotransduction determines the podocyte's response to damage

Project description:Podocytes are terminally differentiated cells at the kidney filtration barrier and exposed to considerable mechanical strain. Podocyte injury causes morphological changes as a result of cytoskeletal reorganizations and failure of the filtration barrier. The transcriptional co-activators YAP/TAZ are tightly controlled through hippo signaling and responsive to mechanical cues. Here, we show that YAP is upregulated upon podocyte injury to activate YAP-dependent target genes. This activation preceded the development of proteinuria. In contrast, similar perturbations of cells in culture did not reveal increased YAP activity but showed a downregulation of YAP/TAZ activity when cells were grown on stiff surface. However, culture of cells on soft matrix or inhibition of stress fiber formation allowed recapitulation of the damage-induced YAP upregulation indicating a mechanotransduction-dependent mechanism of YAP over-activity. Interestingly, increased expression of YAP targets was confirmed in renal biopsies from patients with glomerular disease. Consistently, pharmacological inhibition of YAP/TEAD activity ameliorated glomerular disease in vivo. These data suggest that perturbation of the mechanosensitive hippo signaling pathway may be a therapeutic principle in podocyte disease.

2017-04-19 | PXD003872 | Pride

YAP regulates cell mechanics by controlling focal adhesion assembly

Project description:Hippo effectors YAP/TAZ act as on-off mechanosensing switches by sensing modifications in extracellular matrix (ECM) composition and mechanics. The regulation of their activity has been described so far through a hierarchical model in which elements of Hippo pathway are under the control of Focal Adhesions (FAs). Here we unveiled the molecular mechanism by which cell spreading and RhoA GTPase control FA formation through YAP to stabilize the anchorage of actin cytoskeleton to cell membrane. This mechanism required YAP co-transcriptional function and involved the activation of genes encoding for integrins and FA docking proteins. Tuning YAP transcriptional activity led to the modification of cell mechanics, force development, adhesion strength, determined cell shaping, migration and differentiation. These results provide new insights into the mechanism of YAP mechanosensing activity and qualify Hippo effector as the key determinant of cell mechanics in response to ECM cues.

2017-05-17 | E-MTAB-5217 | biostudies-arrayexpress

RAP2 Mediates Mechanotransduction to Hippo pathway

Project description:Mammalian cells are surrounded by the extracellular matrix (ECM), which regulates intercellular signal transduction and provides structural support to cells. Mechanical forces generated by ECM play a key role in regulating cell behaviors including survival, growth, mobility, and differentiation. However, it is unclear how mechanical forces are sensed by cells and transmit biochemical signals to cell fate-determining transcription factors such as YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif). Here we show the identification of Ras-associated protein 2 (RAP2) as an intracellular signal transducer that senses ECM rigidity and modulates cell survival and growth by negatively regulating YAP/TAZ. Activation of RAP2 by low ECM stiffness or contact inhibition triggers YAP/TAZ phosphorylation. Deletion of RAP2 leads to sustained YAP/TAZ activation in cells that grow on soft matrix or undergo contact inhibition, alters transcription programs initiated by low matrix stiffness, and results in cell transformation and malignant growth. Mechanistically, RAP2 can directly bind to Mitogen-activated protein kinase kinase kinase kinase 4/6/7 (MAP4K4/6/7) or Rho GTPase activating protein 29 (ARHGAP29), both of which lead to LATS1/2 activation and YAP/TAZ inhibition. These findings define a new molecular pathway that transmits mechanical cues to their effectors in the nucleus.

2018-07-09 | GSE98547 | GEO

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