title: Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver.
abstract: Aging is accompanied by physiological impairments, which, in insulin-responsive tissues, including the liver, predispose individuals to metabolic disease. However, the molecular mechanisms underlying these changes remain largely unknown. Here, we analyze genome-wide profiles of RNA and chromatin organization in the liver of young (3 months) and old (21 months) mice. Transcriptional changes suggest that derepression of the nuclear receptors PPARα, PPARγ, and LXRα in aged mouse liver leads to activation of targets regulating lipid synthesis and storage, whereas age-dependent changes in nucleosome occupancy are associated with binding sites for both known regulators (forkhead factors and nuclear receptors) and candidates associated with nuclear lamina (Hdac3 and Srf) implicated to govern metabolic function of aging liver. Winged-helix transcription factor Foxa2 and nuclear receptor corepressor Hdac3 exhibit a reciprocal binding pattern at PPARα targets contributing to gene expression changes that lead to steatosis in aged liver.
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: ibochkis@broadinstitute.org.
authors.forename: Irina M
authors.initials: IM
authors.lastname: Bochkis
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Przybylski
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008099:Liver / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008322:Mammals / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D034881:Nuclear Lamina / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D004268:DNA-Binding Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D006655:Histone Deacetylases; D009707:Nucleosomes; D047493:PPAR alpha; D014157:Transcription Factors; D000099186:Histone Deacetylase 3; C496503:Foxa2 protein, mouse; C089581:Zfp67 protein, mouse