2018-10-182018-10-181932620310.1371/journal.pone.0081186http://hdl.handle.net/11285/630296Thyroid hormone (TH) receptors (TRs) play central roles in metabolism and are major targets for pharmaceutical intervention. Presently, however, there is limited information about genome wide localizations of TR binding sites. Thus, complexities of TR genomic distribution and links between TRβ binding events and gene regulation are not fully appreciated. Here, we employ a BioChIP approach to capture TR genome-wide binding events in a liver cell line (HepG2). Like other NRs, TRβ appears widely distributed throughout the genome. Nevertheless, there is striking enrichment of TRβ binding sites immediately 5′ and 3′ of transcribed genes and TRβ can be detected near 50% of T3 induced genes. In contrast, no significant enrichment of TRβ is seen at negatively regulated genes or genes that respond to unliganded TRs in this system. Canonical TRE half-sites are present in more than 90% of TRβ peaks and classical TREs are also greatly enriched, but individual TRE organization appears highly variable with diverse half-site orientation and spacing. There is also significant enrichment of binding sites for TR associated transcription factors, including AP-1 and CTCF, near TR peaks. We conclude that T3-dependent gene induction commonly involves proximal TRβ binding events but that far-distant binding events are needed for T3 induction of some genes and that distinct, indirect, mechanisms are often at play in negative regulation and unliganded TR actions. Better understanding of genomic context of TR binding sites will help us determine why TR regulates genes in different ways and determine possibilities for selective modulation of TR action. © 2014 Ayers et al.info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/4.0thyroid hormone receptor betatranscription factor AP 1transcription factor CTCFligandprotein bindingRNAthyroid hormone receptor beta3' untranslated region5' untranslated regionanimal experimentanimal tissuearticlebinding kineticsbinding sitecontrolled studygene clustergene controlgene expressiongene repressiongene sequencegene targetinggenetic associationgenetic transcriptiongenetic transfectionhumanhuman cellliver cellmousenonhumannucleotide sequenceprotein analysisprotein functionprotein localizationsequence analysisanimalbinding siteC57BL mousecell linechemistryDNA microarrayDNA responsive elementDNA sequencegene expression regulationgenomeHepG2 cell linelivermetabolismmultigene familyplasmidAnimalsBinding SitesCell LineGene Expression RegulationGenomeHep G2 CellsHumansLigandsLiverMiceMice, Inbred C57BLMultigene FamilyOligonucleotide Array Sequence AnalysisPlasmidsProtein BindingResponse ElementsRNASequence Analysis, DNAThyroid Hormone Receptors beta7 INGENIERÍA Y TECNOLOGÍAArtículo92