Changes in nucleosome occupancy associated with metabolic alterations in aged mammalian liver.

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.

[1]  Hyung Keun Kim,et al.  The effect of age and calorie restriction on HIF-1-responsive genes in aged liver , 2004, Biogerontology.

[2]  Steven Henikoff,et al.  Histone variants — ancient wrap artists of the epigenome , 2010, Nature Reviews Molecular Cell Biology.

[3]  Chad A Shaw,et al.  Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation , 2007, PLoS biology.

[4]  S. Haefliger,et al.  Epigenetic changes play critical role in age‐associated dysfunctions of the liver , 2010, Aging cell.

[5]  Helga Thorvaldsdóttir,et al.  Integrative Genomics Viewer , 2011, Nature Biotechnology.

[6]  M. Guenther,et al.  The SMRT and N-CoR Corepressors Are Activating Cofactors for Histone Deacetylase 3 , 2001, Molecular and Cellular Biology.

[7]  M. Hatta,et al.  Chromatin Opening and Stable Perturbation of Core Histone:DNA Contacts by FoxO1* , 2007, Journal of Biological Chemistry.

[8]  T. Misteli,et al.  Lamin A-Dependent Nuclear Defects in Human Aging , 2006, Science.

[9]  J. Kieft,et al.  Elevated histone expression promotes life span extension. , 2010, Molecular cell.

[10]  Raymond K. Auerbach,et al.  PeakSeq enables systematic scoring of ChIP-seq experiments relative to controls , 2009, Nature Biotechnology.

[11]  Anton Nekrutenko,et al.  Using Galaxy to Perform Large‐Scale Interactive Data Analyses , 2007, Current protocols in bioinformatics.

[12]  Cynthia Kenyon,et al.  Regulation of Aging and Age-Related Disease by DAF-16 and Heat-Shock Factor , 2003, Science.

[13]  Jonathan Schug,et al.  The Nucleosome Map of the Mammalian Liver , 2011, Nature Structural &Molecular Biology.

[14]  Zhaoyu Li,et al.  DANPOS: Dynamic analysis of nucleosome position and occupancy by sequencing , 2013, Genome research.

[15]  N. Friedman,et al.  Substantial Histone Reduction Modulates Genomewide Nucleosomal Occupancy and Global Transcriptional Output , 2011, PLoS biology.

[16]  Jonathan Schug,et al.  PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. , 2008, Genes & development.

[17]  E. Metter,et al.  Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. , 2007, The Journal of clinical endocrinology and metabolism.

[18]  R. Misra,et al.  Hepatocyte expression of serum response factor is essential for liver function, hepatocyte proliferation and survival, and postnatal body growth in mice , 2009, Hepatology.

[19]  H. Stunnenberg,et al.  Genome-Wide Profiling of Liver X Receptor, Retinoid X Receptor, and Peroxisome Proliferator-Activated Receptor α in Mouse Liver Reveals Extensive Sharing of Binding Sites , 2011, Molecular and Cellular Biology.

[20]  M. Birnbaum,et al.  PPARγ contributes to PKM2 and HK2 expression in fatty liver , 2012, Nature Communications.

[21]  D. Savage.  Mouse models of inherited lipodystrophy , 2009, Disease Models & Mechanisms.

[22]  E. Medrano,et al.  The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation , 2011, Hepatology.

[23]  G. Garinis,et al.  DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria. , 2013, Cell metabolism.

[24]  R. Scott,et al.  Senescence represses the nuclear localization of the serum response factor and differentiation regulates its nuclear localization with lineage specificity. , 2001, Journal of cell science.

[25]  J. Workman,et al.  Nucleosome core displacement in vitro via a metastable transcription factor-nucleosome complex. , 1992, Science.

[26]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[27]  L. Timchenko,et al.  GSK3β and aging liver , 2009, Aging.

[28]  D. Umlauf,et al.  Site-specific analysis of histone methylation and acetylation. , 2004, Methods in molecular biology.

[29]  Cory Y. McLean,et al.  GREAT improves functional interpretation of cis-regulatory regions , 2010, Nature Biotechnology.

[30]  Tom H. Cheung,et al.  Chromatin Modifications as Determinants of Muscle Stem Cell Quiescence and Chronological Aging , 2013, Cell reports.

[31]  Mark A. McCormick,et al.  Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity , 2010, Proceedings of the National Academy of Sciences.

[32]  M. Reitman,et al.  Liver Peroxisome Proliferator-activated Receptor γ Contributes to Hepatic Steatosis, Triglyceride Clearance, and Regulation of Body Fat Mass* , 2003, Journal of Biological Chemistry.

[33]  Peter White,et al.  Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress , 2008, Nature Medicine.

[34]  S. Gregory,et al.  LMNA, encoding lamin A/C, is mutated in partial lipodystrophy , 2000, Nature Genetics.

[35]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[36]  Michael Müller,et al.  Peroxisome Proliferator-Activated Receptor Alpha Target Genes , 2010, PPAR research.

[37]  Mikael Bodén,et al.  MEME Suite: tools for motif discovery and searching , 2009, Nucleic Acids Res..

[38]  David Haussler,et al.  The UCSC Genome Browser database: 2014 update , 2013, Nucleic Acids Res..

[39]  Graziano Pesole,et al.  PscanChIP: finding over-represented transcription factor-binding site motifs and their correlations in sequences from ChIP-Seq experiments , 2013, Nucleic Acids Res..

[40]  Hong Wang,et al.  Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration , 2012, Nature Medicine.

[41]  J. Hoeijmakers,et al.  A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis , 2006, Nature.

[42]  J. Hoeijmakers,et al.  Sealing the gap between nuclear DNA damage and longevity , 2009, Molecular and Cellular Endocrinology.

[43]  Andrew J. Wilson,et al.  Hdac3 is essential for the maintenance of chromatin structure and genome stability. , 2010, Cancer cell.

[44]  Colin N. Dewey,et al.  RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome , 2011, BMC Bioinformatics.

[45]  M. Fessler,et al.  Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome , 2009, Current opinion in lipidology.

[46]  S. Hiebert,et al.  Liver‐specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks , 2008, The EMBO journal.

[47]  J. Schug,et al.  Genome-Wide Location Analysis Reveals Distinct Transcriptional Circuitry by Paralogous Regulators Foxa1 and Foxa2 , 2012, PLoS genetics.

[48]  K. Kaestner,et al.  Bile acid-induced inflammatory signaling in mice lacking Foxa2 in the liver leads to activation of mTOR and age-onset obesity. , 2013, Molecular metabolism.

[49]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[50]  Edison T. Liu,et al.  Regulation of Transcription through Acetylation of H3K122 on the Lateral Surface of the Histone Octamer , 2013, Cell.

[51]  Zhiqi Sun,et al.  CIDE proteins and metabolic disorders , 2009, Current opinion in lipidology.

[52]  Daniel J. Blankenberg,et al.  Using Galaxy to Perform Large‐Scale Interactive Data Analyses , 2012, Current protocols in bioinformatics.

[53]  E. Delbarre,et al.  Lamin A/C-promoter interactions specify chromatin state–dependent transcription outcomes , 2013, Genome research.

[54]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[55]  Wyeth W. Wasserman,et al.  A new generation of JASPAR, the open-access repository for transcription factor binding site profiles , 2005, Nucleic Acids Res..

[56]  E. Medrano,et al.  Role of HDAC1 in senescence, aging, and cancer , 2010, Experimental Gerontology.

[57]  E. Eyras,et al.  Nucleosome-driven transcription factor binding and gene regulation. , 2013, Molecular cell.

[58]  Dennis E. Discher,et al.  Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation , 2013, Science.