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A Zeb1 Hdac2 eNOS feedback circuitry identifies early cardiovascular precursors in naïve mouse embryonic stem cells (RNA-Seq)

ABSTRACT: Soon after release from stemness, a relevant portion of mouse embryonic stem cells (mES), kept in naïve state by MEK inhibitor, GSK3 inhibitor and LIF (2i/L), expresses endothelial nitric oxide synthase (eNOS) and endogenously synthesizes nitric oxide (NO). In this condition, an eNOS/NO-positive subpopulation (ESNO+) has been recognized by 4-amino-5-methylamino-2′,7′-difluorescein (DAF) fluorescence. Sorted ESNO+ cells expressed high levels of mesendodermal markers and efficiently generated cardiovascular precursors compared to eNOS/NO-negative cells (ESNO-). Mechanistically, the endogenous NO production deter- mined a rapid S-nitrosylation of Hdac2, a post-translational modification that compromised Hdac2 association with the transcription repression factor Zeb1. This condition destabilized Zeb1/chromatin interaction with genomic loci encoding for mesendodermal genes. Remarkably, Zeb1 or Hdac2 targeting activated an unscheduled transcription of mesendodermal lineage-associated genes in naïve mES revealing the Hdac2-Zeb1 pathway important for stemness maintenance in 2i/L. In contrast, eNOS targeting significantly reduced the endogenous NO production preventing the activation of mesendodermal gene transcription.

ORGANISM(S): Mus musculus

PROVIDER: GSE104647 | GEO | 2018/10/31

REPOSITORIES: GEO

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Project description:Chen2006 - Nitric Oxide Release from Endothelial Cells This model is described in the article: Theoretical analysis of biochemical pathways of nitric oxide release from vascular endothelial cells. Chen K, Popel AS. Free Radic. Biol. Med. 2006 Aug; 41(4): 668-680 Abstract: Vascular endothelium expressing endothelial nitric oxide synthase (eNOS) produces nitric oxide (NO), which has a number of important physiological functions in the microvasculature. The rate of NO production by the endothelium is a critical determinant of NO distribution in the vascular wall. We have analyzed the biochemical pathways of NO synthesis and formulated a model to estimate NO production by the microvascular endothelium under physiological conditions. The model quantifies the NO produced by eNOS based on the kinetics of NO synthesis and the availability of eNOS and its intracellular substrates. The predicted NO production from microvessels was in the range of 0.005-0.1 microM/s. This range of predicted values is in agreement with some experimental values but is much lower than other rates previously measured or estimated from experimental data with the help of mathematical modeling. Paradoxical discrepancies between the model predictions and previously reported results based on experimental measurements of NO concentration in the vicinity of the arteriolar wall suggest that NO can also be released through eNOS-independent mechanisms, such as catalysis by neuronal NOS (nNOS). We also used our model to test the sensitivity of NO production to substrate availability, eNOS concentration, and potential rate-limiting factors. The results indicated that the predicted low level of NO production can be attributed primarily to a low expression of eNOS in the microvascular endothelial cells. This model is hosted on BioModels Database and identified by: BIOMD0000000676. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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A Zeb1 Hdac2 eNOS feedback circuitry identifies early cardiovascular precursors in naïve mouse embryonic stem cells (RNA-Seq)

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