Fig. 3.

Key driver MTHFD2 and oxPAPC induce endothelial Bayesian amino acid subnetwork. a Network view of the oxPAPC Bayesian subnetwork with MTHFD2 as key driver. Nodes that belong to indicated significantly overrepresented canonical gene set categories are highlighted respectively. Node size reflects out-degree. b Schematic diagram of enzymes within the MTHFD2 network (blue) that are directly or indirectly involved in serine, glycine, cysteine, methionine, aspartate, and asparagine (orange) interconversion as well as interconversion of tetrahydrofolates (THF) inside mitochondria (green). CBS: Cystathionine-Beta-Synthase, PCK2: Phosphoenolpyruvate Carboxykinase 2, GOT1 Glutamic-Oxaloacetic Transaminase 1, GLDC: Glycine Decarboxylase, ASNS: Asparagine Synthetase. c−l Experimental validation of the MTHFD2 network as assessed by quantitative RT-PCR. HAEC with and without knockdown of the key driver MTHFD2 or the downstream node PSAT1 were exposed to medium (1% FCS) with (oxP) or without (Ct) oxPAPC for 4 h (n ≥ 4). Genes belonging to the MTHFD2 network are framed by the color of the corresponding gene set category as in a. Data are represented as mean ± SEM, *p ≤ 0.05 (MTHFD2 or PSAT1 vs Control siRNA), ^#p ≤ 0.05 (oxP vs Ct) (ANOVA with Bonferroni post-hoc test). MTHFD2: Methylenetetrahydrofolate Dehydrogenase (NADP + Dependent) 2-Methenyltetrahydrofolate Cyclohydrolase, SHMT2: serine hydroxymethyltransferase 2, PHGDH: phosphoglycerate dehydrogenase, PSAT1: phosphoserine aminotransferase 1, CEBPB: CCAAT/Enhancer Binding Protein Beta, GARS: Glycyl-TRNA Synthetase, CARS Cysteinyl-TRNA Synthetase, SLC7A5: Solute Carrier Family 7 Member 5, SLC7A1: Solute Carrier Family Member 1, MTHFD1L: Methylenetetrahydrofolate Dehydrogenase (NADP + Dependent) 1-Like