Glucose-6-phosphate dehydrogenase variants modify 3D genomic organization to suppress maladaptive gene expression and vascular disease

The 3D genome architecture is a higher-order organization of chromosomes within the nucleus that is critical to the control of epigenomic modifications. However, our knowledge regarding the role of 3D genomic organization in the regulation of vascular gene expression and function is lacking. In the present study, CRISPR-engineered rats modelled after two common polymorphisms (S188F and N126D) in human glucose-6-phosphate dehydrogenase (G6PD) revealed modifications to the 3D genome in aortas from rats expressing a deficient G6PD variant (S188F), but not a non-deficient one (N126D), is associated with: 1] up-regulated expression of TET enzymes that augmented expression of genes encoding antiproliferative proteins, 2] suppressed expression of genes encoding inflammatory/thrombotic/fibrotic proteins, and 3] reduced angiotensin II-induced aortic stiffness and hypertension. G6PD interacted with MATRIN-3, a nuclear matrix/scaffold protein, and a deficient G6PD variant increased the relative abundance of MATR3 and CCCTC-binding factors, potentially modifying 3D-genome structure. Additionally, G6PD deficiency-induced enrichment of H3K27ac likely influences the establishment and maintenance of the 3D genome. Therefore, we propose that the nexus between metabolism and the 3D genome regulates arterial gene expression and vascular disease.