title: Metabolomics reveals a role for the chromatin-binding protein HMGN5 in glutathione metabolism.
abstract: High mobility group nucleosome-binding protein 5 (HMGN5) is a chromatin architectural protein that binds specifically to nucleosomes and reduces the compaction of the chromatin fiber. The protein is present in most vertebrate tissues however the physiological function of this protein is unknown. To examine the function of HMGN5 in vivo, mice lacking the nucleosome-binding domain of HMGN5 were generated and characterized. Serological analysis revealed that compared to wild-type littermates (Hmgn5(+/Y)), mice with a targeted mutation in the HMGN5 gene (Hmgn5(tm1/Y)), had elevated serum albumin, non-HDL cholesterol, triglycerides, and alanine transaminase, suggesting mild hepatic abnormalities. Metabolomics analysis of liver extracts and urine revealed clear differences in metabolites between Hmgn5(tm1/Y) and their Hmgn5(+/Y) littermates. Hmgn5(tm1/Y) mice had a significant increase in hepatic glutathione levels and decreased urinary concentrations of betaine, phenylacetylglycine, and creatine, all of which are metabolically related to the glutathione precursor glycine. Microarray and qPCR analysis revealed that expression of two genes affecting glutathione metabolism, glutathione peroxidase 6 (Gpx6) and hexokinase 1 (Hk1), was significantly decreased in Hmgn5(tm1/Y) mouse liver tissue. Analysis of chromatin structure by DNase I digestion revealed alterations in the chromatin structure of these genes in the livers of Hmgn5(tm1/Y) mice. Thus, functional loss of HMGN5 leads to changes in transcription of Gpx6 and Hk1 that alter glutathione metabolism.
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Ciappio
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Rochman
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Takashi
authors.initials: T
authors.lastname: Furusawa
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Bonzo
authors.affiliation: Neural Development Section, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Bustin
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D023061:Gene Order; D018390:Gene Targeting; D005978:Glutathione / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D024001:HMGN Proteins / Q000378:metabolism*; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding
chemical_list: D002843:Chromatin; D024001:HMGN Proteins; C498963:Hmgn5 protein, mouse; D005979:Glutathione Peroxidase; C515658:HK1 protein, mouse; D006593:Hexokinase; D005978:Glutathione