A Global View of Transcriptional Regulation by Nuclear Receptors: Gene Expression, Factor Localization, and DNA Sequence Analysis

Abstract

Recent genomic analyses of transcription factor binding, histone modification, and gene expression have provided a global view of transcriptional regulation by nuclear receptors (NRs) that complements an existing large body of literature on gene-specific studies. The picture emerging from these genomic studies indicates that NRs bind at promoter-proximal and promoter-distal enhancers in conjunction with other transcription factors (e.g., activator protein-1, Sp1 and FOXA1). This binding promotes the recruitment of coregulators that mediate the posttranslational modification of histones at promoters and enhancers. Ultimately, signaling through liganded NRs stimulates changes in the occupancy of RNA polymerase II (Pol II) or the activation of preloaded Pol II at target promoters. Chromosomal looping and/or Pol II tracking may underlie promoter-enhancer communication. Interestingly, the direct target genes of NR signaling represent a limited subset of all the genes regulated by NR ligands, with the rest being regulated through secondary effects. As suggested by previous gene-specific analyses, NR-mediated outcomes are highly cell type-and promoter-specific, highlighting the complexity of transcriptional regulation by NRs and the value of genomic analyses for identifying commonly shared patterns. Overall, NRs share common themes in their patterns of localization and transcriptional regulation across mammalian genomes. In this review, we provide an overview of recent advances in the understanding of NR-mediated transcription garnered from genomic analyses of gene expression, factor localization, and target DNA sequences. Received November 21st, 2007; Accepted February 7th, 2008; Published February 15th, 2008 | Abbreviations: AcH: acetylated histones H3/H4; AcH3K9/14: H3 acetylated at lysines 9 and 14; AP-1: activator protein-1; AR: androgen receptor; CBP: CREB binding protein; ChIP: chromatin immunoprecipitation; CREB: cAMP response element binding protein; DSL: DNA selection and ligation; E2: estradiol; ERα: estrogen receptor α; ERE: estrogen response elements; ERR: estrogen-related receptor; GR: glucocorticoid receptor; H3K4me1: H3 mono-methylated at lysine 4; H3K4me2: H3 di-methylated at lysine 4; H3K4me3: H3 tri-methylated at lysine 4; H3K9me3: H3 tri-methylated at lysine 9; H3K79me2: H3 di-methylated at lysine 79; NR: nuclear receptor; PET: paired-end tag; Pol II: RNA polymerase II; qPCR: quantitative real-time polymerase chain reaction; SAGE: serial analysis of gene expression; SRC: steroid receptor coactivator; TSS: transcription start site; VDR: vitamin D receptor | Copyright © 2008, Kininis and Kraus. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited.Cite this article: Nuclear Receptor Signaling (2008) 6, e005 IntroductionThe spatial and temporal regulation of gene expression is an important means by which...

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