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  • 1
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    Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-05-17
    Description: Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell-type-specific gene expression programs, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell-lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally and functionally distinct classes of enhancer. Consequently, FoxA1 downregulation, an unfavourable prognostic sign in certain advanced prostate tumours, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA) based on global nuclear run-on sequencing (GRO-seq) analysis, with a unique class apparently requiring no nucleosome remodelling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117022/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Dong -- Garcia-Bassets, Ivan -- Benner, Chris -- Li, Wenbo -- Su, Xue -- Zhou, Yiming -- Qiu, Jinsong -- Liu, Wen -- Kaikkonen, Minna U -- Ohgi, Kenneth A -- Glass, Christopher K -- Rosenfeld, Michael G -- Fu, Xiang-Dong -- DK01847/DK/NIDDK NIH HHS/ -- DK074868/DK/NIDDK NIH HHS/ -- DK37949/DK/NIDDK NIH HHS/ -- GM049369/GM/NIGMS NIH HHS/ -- HG004659/HG/NHGRI NIH HHS/ -- NS34934/NS/NINDS NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 DK074868-05/DK/NIDDK NIH HHS/ -- P30 AG038072/AG/NIA NIH HHS/ -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-10/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-30/DK/NIDDK NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 GM049369/GM/NIGMS NIH HHS/ -- R01 GM049369-17/GM/NIGMS NIH HHS/ -- R01 HG004659/HG/NHGRI NIH HHS/ -- R01 HG004659-03/HG/NHGRI NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 HL065445-12/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-23/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- R37 DK039949-28/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 15;474(7351):390-4. doi: 10.1038/nature10006.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21572438" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Line, Tumor ; Cell Lineage ; Dihydrotestosterone/pharmacology ; Down-Regulation ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Genome, Human/genetics ; HEK293 Cells ; Hepatocyte Nuclear Factor 3-alpha/deficiency/genetics/*metabolism ; Histones/metabolism ; Humans ; Kallikreins ; Male ; Prostate-Specific Antigen ; Prostatic Neoplasms/metabolism/pathology ; RNA, Small Interfering/genetics/metabolism ; RNA, Untranslated/*genetics ; Receptors, Androgen/*metabolism ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    9p21 DNA variants associated with coronary artery disease impair interferon-gamma signalling response (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-02-11
    Description: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the 9p21 gene desert associated with coronary artery disease (CAD) and type 2 diabetes. Despite evidence for a role of the associated interval in neighbouring gene regulation, the biological underpinnings of these genetic associations with CAD or type 2 diabetes have not yet been explained. Here we identify 33 enhancers in 9p21; the interval is the second densest gene desert for predicted enhancers and six times denser than the whole genome (P 〈 6.55 x 10(-33)). The CAD risk alleles of SNPs rs10811656 and rs10757278 are located in one of these enhancers and disrupt a binding site for STAT1. Lymphoblastoid cell lines homozygous for the CAD risk haplotype show no binding of STAT1, and in lymphoblastoid cell lines homozygous for the CAD non-risk haplotype, binding of STAT1 inhibits CDKN2BAS (also known as CDKN2B-AS1) expression, which is reversed by short interfering RNA knockdown of STAT1. Using a new, open-ended approach to detect long-distance interactions, we find that in human vascular endothelial cells the enhancer interval containing the CAD locus physically interacts with the CDKN2A/B locus, the MTAP gene and an interval downstream of IFNA21. In human vascular endothelial cells, interferon-gamma activation strongly affects the structure of the chromatin and the transcriptional regulation in the 9p21 locus, including STAT1-binding, long-range enhancer interactions and altered expression of neighbouring genes. Our findings establish a link between CAD genetic susceptibility and the response to inflammatory signalling in a vascular cell type and thus demonstrate the utility of genome-wide association study findings in directing studies to novel genomic loci and biological processes important for disease aetiology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079517/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079517/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harismendy, Olivier -- Notani, Dimple -- Song, Xiaoyuan -- Rahim, Nazli G -- Tanasa, Bogdan -- Heintzman, Nathaniel -- Ren, Bing -- Fu, Xiang-Dong -- Topol, Eric J -- Rosenfeld, Michael G -- Frazer, Kelly A -- 1R21CA152613-01/CA/NCI NIH HHS/ -- 1U54RR025204/RR/NCRR NIH HHS/ -- 1UL1RR025774/RR/NCRR NIH HHS/ -- 1UL1RR031980-01/RR/NCRR NIH HHS/ -- CA97134/CA/NCI NIH HHS/ -- DK018477/DK/NIDDK NIH HHS/ -- DK074868/DK/NIDDK NIH HHS/ -- DK39949/DK/NIDDK NIH HHS/ -- DK74686/DK/NIDDK NIH HHS/ -- HL065445/HL/NHLBI NIH HHS/ -- L65445/PHS HHS/ -- NS34934/NS/NINDS NIH HHS/ -- P01 AG025204/AG/NIA NIH HHS/ -- P01 AG025204-01/AG/NIA NIH HHS/ -- R01 CA097134/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-29/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 HL065445-12/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R21 CA152613/CA/NCI NIH HHS/ -- R21 CA152613-01/CA/NCI NIH HHS/ -- R21 CA152613-02/CA/NCI NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- U01 HL107442/HL/NHLBI NIH HHS/ -- UL1 RR025774/RR/NCRR NIH HHS/ -- UL1 RR025774-01/RR/NCRR NIH HHS/ -- UL1 RR031980/RR/NCRR NIH HHS/ -- UL1 RR031980-01/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 10;470(7333):264-8. doi: 10.1038/nature09753.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Rady's Children's Hospital, University of California at San Diego, School of Medicine, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307941" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Cell Line ; Chromatin/drug effects/genetics/metabolism ; Chromosomes, Human, Pair 9/*genetics ; Conserved Sequence/genetics ; Coronary Artery Disease/*genetics ; Cyclin-Dependent Kinase Inhibitor p15/genetics ; Diabetes Mellitus, Type 2/genetics ; Endothelial Cells/drug effects/metabolism ; Enhancer Elements, Genetic/*genetics ; European Continental Ancestry Group/genetics ; Gene Expression Regulation/drug effects/genetics ; Gene Knockdown Techniques ; Genetic Predisposition to Disease/*genetics ; *Genetic Variation ; Genome-Wide Association Study ; Haplotypes/genetics ; HeLa Cells ; Humans ; Interferon-alpha/genetics ; Interferon-gamma/*pharmacology ; Linkage Disequilibrium ; Male ; Polymorphism, Single Nucleotide/genetics ; Protein Binding/drug effects ; Purine-Nucleoside Phosphorylase/genetics ; STAT1 Transcription Factor/biosynthesis/deficiency/genetics/metabolism ; Signal Transduction/*drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
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