Targeted disruption of the nucleosomal binding protein HMGN5 results in altered glutathione metabolism and mild hepatic dysfunction

Abstract

High mobility group nucleosome‐binding protein 5 (HMGN5) is a chromatin architectural protein that regulates gene expression by decompacting higher‐order chromatin structure; however, the physiological role of this protein is unknown. To examine the function of HMGN5 in vivo, we generated mice lacking the chromatin binding domain of the protein. Compared to wild type littermates, male Hmgn5−/Y mice had elevated serum albumin (p=0.03), fasting non‐HDL cholesterol (p=0.03), fasting triglycierides (p=0.05), and alanine transaminase (p=0.08), suggesting a mild hepatic dysfunction. An UPLC‐QTOF‐MS‐based metabolomic study in Hmgn5−/Y mice identified a 41% increase in hepatic glutathione (p=0.02) and significantly (p<0.05) decreased urinary concentrations of compounds related to the glutathione precursor glycine, such as betaine (−62%), phenylacetylglycine (−50%), and creatine (−42%). Microarray analysis and validation by real‐time PCR revealed that the expression of two genes affecting glutathione function, Gpx6 and Hk1, was significantly (p<0.05) decreased in Hmgn5−/Y mouse liver tissue. In sum, these data suggest that functional loss of the chromatin remodeling protein HMGN5 leads to transcriptional changes that alter glutathione metabolism resulting in mild hepatic dysfunction.Grant Funding Source: NIH/NCI/CCR Intramural Program