title: Epigenetic priming of inflammatory response genes by high glucose in adipose progenitor cells.
abstract: Cellular metabolism confers wide-spread epigenetic modifications required for regulation of transcriptional networks that determine cellular states. Mesenchymal stromal cells are responsive to metabolic cues including circulating glucose levels and modulate inflammatory responses. We show here that long term exposure of undifferentiated human adipose tissue stromal cells (ASCs) to high glucose upregulates a subset of inflammation response (IR) genes and alters their promoter histone methylation patterns in a manner consistent with transcriptional de-repression. Modeling of chromatin states from combinations of histone modifications in nearly 500 IR genes unveil three overarching chromatin configurations reflecting repressive, active, and potentially active states in promoter and enhancer elements. Accordingly, we show that adipogenic differentiation in high glucose predominantly upregulates IR genes. Our results indicate that elevated extracellular glucose levels sensitize in ASCs an IR gene expression program which is exacerbated during adipocyte differentiation. We propose that high glucose exposure conveys an epigenetic 'priming' of IR genes, favoring a transcriptional inflammatory response upon adipogenic stimulation. Chromatin alterations at IR genes by high glucose exposure may play a role in the etiology of metabolic diseases.
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Torunn
authors.initials: T
authors.lastname: Rønningen
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Akshay
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Reiner
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway. Electronic address: philc@medisin.uio.no.
authors.forename: Philippe
authors.initials: P
authors.lastname: Collas
authors.affiliation: Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, and Norwegian Center for Stem Cell Research, Oslo University Hospital, Oslo, Norway. Electronic address: j.o.moskaug@medisin.uio.no.
authors.forename: Jan Øivind
authors.initials: JØ
authors.lastname: Moskaug
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D044127:Epigenesis, Genetic; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D002843:Chromatin; D005947:Glucose
keywords: Adipose stem cell; Chromatin; Gene expression; Glucose; Histone modification; Inflammation