title: Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells.
abstract: Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.
authors: Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.
authors: Radmila
authors: R
authors: Feldmann
authors: Cornelius
authors: C
authors: Fischer
authors: Vitam
authors: V
authors: Kodelja
authors: Sarah
authors: S
authors: Behrens
authors: Stefan
authors: S
authors: Haas
authors: Martin
authors: M
authors: Vingron
authors: Bernd
authors: B
authors: Timmermann
authors: Anne
authors: A
authors: Geikowski
authors: Sascha
authors: S
authors: Sauer
mesh_terms: D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D024363:Transcription Initiation Site; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
references: Genome Biol. 2009;10(3):R25
references: 19261174
references: Arterioscler Thromb Vasc Biol. 1995 May;15(5):551-61
references: 7749869
references: J Biol Chem. 2010 Mar 19;285(12):9221-32
references: 20080977
references: Database (Oxford). 2011 Oct 19;2011:bar031
references: 22012987
references: Biochem Pharmacol. 2006 Feb 14;71(4):453-63
references: 16325781
references: Bioinformatics. 2011 Feb 1;27(3):431-2
references: 21149340
references: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):9880-5
references: 18599447
references: Curr Protoc Hum Genet. 2011 Oct;Chapter 18:Unit18.6
references: 21975940
references: FEBS J. 2011 Jul;278(13):2182-210
references: 21501387
references: Nat Rev Genet. 2009 Sep;10(9):605-16
references: 19668247
references: Nat Protoc. 2011 Dec 15;7(1):45-61
references: 22179591
references: Nature. 2005 Oct 13;437(7061):1032-7
references: 16136080
references: Nat Genet. 2011 Mar;43(3):264-8
references: 21258342
references: Bioinformatics. 2010 Sep 1;26(17):2204-7
references: 20639541
references: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7257-62
references: 22509006
references: Nucleic Acids Res. 2011 Mar;39(4):e25
references: 21113027
references: Nat Rev Genet. 2005 Jun;6(6):465-76
references: 15931170
references: Bioinformatics. 2011 Jun 15;27(12):1696-7
references: 21486936
references: J Lipid Res. 2010 May;51(5):900-6
references: 20388921
references: Nucleic Acids Res. 2012 Jan;40(Database issue):D1036-40
references: 22058129
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D876-82
references: 20959295
references: Nat Protoc. 2009;4(1):44-57
references: 19131956
references: Gut. 2005 Dec;54(12):1776-81
references: 16162682
references: Mol Cell Endocrinol. 2011 Mar 1;334(1-2):39-48
references: 20615451
references: Methods. 2009 Jul;48(3):233-9
references: 19303047
references: Nucleic Acids Res. 2011 Mar;39(6):e35
references: 21177645
references: Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
references: 16381927
references: Cell Metab. 2010 Feb 3;11(2):125-35
references: 20142100
references: Nucleic Acids Res. 2011 Jan;39(Database issue):D856-60
references: 21075797
references: FEBS Lett. 2004 Jul 16;570(1-3):97-101
references: 15251447
references: Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14759-64
references: 17804806
references: Proc Natl Acad Sci U S A. 1999 Jan 5;96(1):266-71
references: 9874807
references: Bioinformatics. 2009 Oct 1;25(19):2605-6
references: 19689956
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references: 19474294
references: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):2926-31
references: 20133639
references: Cell. 2001 Feb 23;104(4):503-16
references: 11239408
references: PLoS One. 2010 Sep 29;5(9):
references: 20927376
references: Experientia. 1991 Jan 15;47(1):22-31
references: 1999239
references: Circ Res. 2011 Apr 15;108(8):985-95
references: 21350215
references: Biochem Biophys Res Commun. 2010 Nov 19;402(3):477-82
references: 20951680
references: Mol Cell Biol. 2001 Nov;21(22):7558-68
references: 11604492
references: Arterioscler Thromb Vasc Biol. 2005 Mar;25(3):622-7
references: 15625283
references: BMC Genomics. 2012 Jan 31;13:50
references: 22292898
references: Proc Natl Acad Sci U S A. 2001 Jan 16;98(2):507-12
references: 11149950
references: BMC Plant Biol. 2010 Nov 05;10:238
references: 21050490
references: Nucleic Acids Res. 2003 Jan 1;31(1):374-8
references: 12520026
references: Genome Biol. 2008;9(9):R137
references: 18798982
references: Cell. 2011 Apr 29;145(3):341-55
references: 21529710
references: FEBS Lett. 2003 Feb 11;536(1-3):6-11
references: 12586329
references: Mol Cell. 2010 May 28;38(4):576-89
references: 20513432
references: Nature. 2009 May 7;459(7243):108-12
references: 19295514
references: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11896-901
references: 12193651
references: Biophys J. 2010 Apr 7;98(7):1247-56
references: 20371324
references: Trends Endocrinol Metab. 2011 Aug;22(8):333-43
references: 21646028
references: Genes Dev. 1997 Feb 1;11(3):289-98
references: 9030682
references: Nat Rev Genet. 2008 May;9(5):356-69
references: 18398418
references: Genes Dev. 2007 Dec 1;21(23):3027-43
references: 18056419
references: Mol Cell Biol. 2012 Feb;32(4):852-67
references: 22158963
references: Science. 2001 May 18;292(5520):1310-2
references: 11360986
references: Trends Pharmacol Sci. 2012 Jul;33(7):394-404
references: 22541735
references: Mol Cell. 2009 May 14;34(4):510-8
references: 19481530
references: PLoS Comput Biol. 2012 May;8(5):e1002529
references: 22693437
references: Bioinformatics. 2012 Oct 1;28(19):2517-9
references: 22829625
references: J Med Chem. 2002 May 9;45(10):1963-6
references: 11985463
references: Cell Metab. 2011 Apr 6;13(4):461-468
references: 21459330
references: Mol Med. 2010 Sep-Oct;16(9-10):389-99
references: 20498921
references: Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):1082-7
references: 20080587
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D412-6
references: 18940858
references: Cell. 2008 Jan 25;132(2):311-22
references: 18243105
references: Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1513-8
references: 20631351