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Glucose metabolism induced chromatin remodeling in pulmonary artery endothelial cell [ChIP-Seq]

ABSTRACT: Maintaining endothelial cells (EC) as a monolayer in the vessel wall depends on a gene expression profile and the metabolic state, features influenced by contact with neighboring cells eg, pericytes and smooth muscle cells (SMC). Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) signaling disrupts EC metabolism and monolayer formation and is associated with vascular diseases such as pulmonary arterial hypertension. We show that BMPR2 in either EC or SMC is required for contact-dependent activation of Notch1 in EC. Notch1, through the glycolysis inducer PFKFB3, mediates an increase in the citrate pool and histone acetylation required for Notch1 and MYC target gene expression. This maintains Notch1-dependent EC proliferative capacity, coordinating with Notch1 activation of mitochondria. We report how Notch1 and p300 binding to chromatin and H3K27ac status are influenced by glucose metabolism and regulate gene expression in endothelial cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE89786 | GEO | 2019/03/18

REPOSITORIES: GEO

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Project description:Chronic lymphocytic leukemic B cells (CLL) reside in close contact with activated endothelial cells (EC) in infiltrated tissues. Here, we investigated the interactions between EC and CLL cells, highlighting molecular networks involved in this cellular crosstalk. We co-cultured purified CLL cells on HUVEC monolayer (HC) or in medium alone. We found that EC protected CLL from spontaneous apoptosis. A 2.2-fold increase in relative viability in IGHV mutated CLL and a 6.1-fold increase in IGHV unmutated CLL was detected in co-culture. Moreover, the endothelial cell layer decreased the in vitro sensitivity of CLL cells to Fludarabine-induced apoptosis. Physical contact with EC is essential for protection to apoptosis. The insertion of a microporous membrane or blocking adhesion with anti-CD106 and anti-CD18 antibodies determined the complete abrogation of apoptosis protection. On the other hand, a reduction of apoptosis was measured in CLL cells cultured with conditioned medium collected from HC, implying that survival is partially mediated by soluble factors. Overall 1944 genes were modulated in CLL by co-culture. The EC contact seem to determine on CLL a kind of microenvironmental-driven angiogenic switch, improve the secretion of cytokines regulating tissue elements such as stromal cells and macrophages and also increase anti-apoptotic molecules. Our study support the line of evidence indicating endothelial cells as a major player in the CLL-infiltrated microenvironments are able to create a vicious cycle of cooperation that strongly sustains leukemic cell survival, protects CLL from drug-induced apoptosis and widely modifies CLL phenotype. Large-scale gene expression profiling (GEP) was performed on total RNA extracted from purified CD19+ cells isolated from 9 individual CLL patients which were separated in 3 experimental subsets: (i) freshly isolated cells (CLL baseline), (ii) CLL cells cultured in medium alone for 48 hours (CLL only) and (iii) CLL cells co-cultured 48h on HUVEC layer (CLL HC).

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Glucose metabolism induced chromatin remodeling in pulmonary artery endothelial cell [ChIP-Seq]

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