title: High-density P300 enhancers control cell state transitions.
abstract: BACKGROUND
  Transcriptional enhancers are frequently bound by a set of transcription factors that collaborate to activate lineage-specific gene expression. Recently, it was appreciated that a subset of enhancers comprise extended clusters dubbed stretch- or super-enhancers (SEs). These SEs are located near key cell identity genes, and enriched for non-coding genetic variations associated with disease. Previously, SEs have been defined as having the highest density of Med1, Brd4 or H3K27ac by ChIP-seq. The histone acetyltransferase P300 has been used as a marker of enhancers, but little is known about its binding to SEs.
  
  
  RESULTS
  We establish that P300 marks a similar SE repertoire in embryonic stem cells as previously reported using Med1 and H3K27ac. We also exemplify a role for SEs in mouse T helper cell fate decision. Similarly, upon activation of macrophages by bacterial endotoxin, we found that many SE-associated genes encode inflammatory proteins that are strongly up-regulated. These SEs arise from small, low-density enhancers in unstimulated macrophages. We also identified expression quantitative trait loci (eQTL) in human monocytes that lie within such SEs. In macrophages and Th17 cells, inflammatory SEs can be perturbed either genetically or pharmacologically thus revealing new avenues to target inflammation.
  
  
  CONCLUSIONS
  Our findings support the notion that P300-marked SEs can help identify key nodes of transcriptional control during cell fate decisions. The SE landscape changes drastically during cell differentiation and cell activation. As these processes are crucial in immune responses, SEs may be useful in revealing novel targets for treating inflammatory diseases.
authors.affiliation: Integrative Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. steven.witte@nih.gov.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. steven.witte@nih.gov.
authors.forename: Steven
authors.initials: S
authors.lastname: Witte
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. abradley@sanger.ac.uk.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
authors.affiliation: EMBL - European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK. aje@ebi.ac.uk.
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Enright
authors.affiliation: Integrative Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Stefan.Muljo@nih.gov.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Muljo
mesh_terms: D000818:Animals; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D040641:Quantitative Trait Loci / Q000235:genetics
chemical_list: D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human