title: Liver ChIP-seq analysis in FGF19-treated mice reveals SHP as a global transcriptional partner of SREBP-2.
abstract: BACKGROUND
  Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, small heterodimer partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis.
  
  
  RESULTS
  The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels.
  
  
  CONCLUSIONS
  This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Sangwon
authors.initials: S
authors.lastname: Byun
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Sunmi
authors.initials: S
authors.lastname: Seok
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Kemper
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. jianma@illinois.edu.|Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. jianma@illinois.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. jongsook@illinois.edu.
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism; D001665:Binding Sites; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics; D047369:Chromatin Immunoprecipitation / Q000379:methods; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D050888:Heat-Shock Proteins, Small / Q000235:genetics* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D001647:Bile Acids and Salts; D050888:Heat-Shock Proteins, Small; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D002784:Cholesterol