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Mechanical shear stress alters NOS3 interacted chromosome conformation [4C-seq]

ABSTRACT: The optimal expression of endothelial nitric oxide synthase (eNOS), the hallmark of endothelial homeostasis, is vital to vascular function. Dynamically regulated by various stimuli, eNOS expression is modulated at transcriptional, post-transcriptional, and post-translational levels. However, epigenetic modulations of eNOS, particularly through long non-coding RNAs (lncRNAs) and chromatin remodeling, remain to be explored. Here we identified an enhancer-associated lncRNA that enhances eNOS expression” (LEENE). Combining RNA-sequencing and chromatin conformation capture methods, we demonstrated that LEENE is co-regulated with eNOS and that its enhancer resides in proximity to eNOS promoter in endothelial cells (ECs). Deletion of LEENE enhancer locus decreases the LEEN-eNOS proximal association and eNOS mRNA level. Inhibition of LEENE using locked nucleic acids (LNA) decreases eNOS expression and monocyte adhesion to ECs, whereas overexpression of LEENE increases eNOS expression and eNOS-derived NO in ECs. Mechanistically, LEENE facilitates the recruitment of RNA Pol II to the eNOS promoter to enhance eNOS nascent RNA transcription. Our findings unravel a new layer in eNOS regulation and provide novel insights into cardiovascular regulation involving endothelial function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103649 | GEO | 2017/10/18

SECONDARY ACCESSION(S): PRJNA403843

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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Mechanical shear stress alters NOS3 interacted chromosome conformation [4C-seq]

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