NRF2 pathway activation reverts high-glucose-induced transcriptional memory in endothelial cells

Various diabetes complications, including nephropathy, retinopathy, and cardiovascular disease, arise from vascular dysfunction. In this context, it has been observed that past hyperglycaemic events can induce long-lasting transcriptional changes, a phenomenon termed "metabolic memory". Yet, the underlying mechanisms driving these persistent effects are not fully characterized. In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high glucose exposure in human endothelial cells (ECs). We found that cells exposed to a transient high glucose episode had decreased glycolytic and oxygen consumption rates. Transcriptional profiling indicated that high glucose exposure induced substantial changes in the expression of genes belonging to pathways known to be impaired in diabetes, such as TGF-beta, TNF, FoxO, p53, and NRF2 pathways, many of which were retained after normalization of glucose concentrations. Furthermore, analysis of chromatin accessibility showed that transient hyperglycaemia can induce persistent modifications in the accessibility landscape, with the majority of differentially accessible regions located in non-promoter regions. Some of these regions were identified as putative enhancers with neighbouring genes persistently altered after transient high glucose exposure. Finally, we showed that activation of the NRF2 pathway through either NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, was able to substantially revert the glucose-induced transcriptional memory in ECs. Our findings demonstrate that transient high glucose can induce persistent changes in both the transcriptomic and chromatin accessibility profiles of ECs, and that pharmacological NRF2 pathway activation is able to prevent and revert the high-glucose-induced transcriptional memory. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=173 SRC="FIGDIR/small/557207v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@b9c938org.highwire.dtl.DTLVardef@1498a43org.highwire.dtl.DTLVardef@1146ab5org.highwire.dtl.DTLVardef@169bfca_HPS_FORMAT_FIGEXP M_FIG C_FIG