High-density P300 enhancers control cell state transitions

BMC Genomics

Research Article

Anton J. Enright¹  Stefan A. Muljo²  Steven Witte³  Allan Bradley⁴ 

[1] EMBL - European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK;Integrative Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;Integrative Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK;Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK;

关键词: Transcriptional regulation;    Lysine acetylation;    Epigenetics;    Long non-coding RNA;    Systems biology;    Inflammation;    Cell differentiation;    Super-enhancers;   

DOI  :  10.1186/s12864-015-1905-6

 received in 2015-04-01, accepted in 2015-09-08,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundTranscriptional 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Witte et al. 2015