Epigenetic determination of a cell-specific gene expression program by ATF-2 and the histone variant macroH2A.
Transcriptional activation of the interleukin-8 (IL-8) gene is restricted to distinct cell types, although the transcriptional regulatory proteins controlling IL-8 gene expression are ubiquitous. We show that cell-specific transcription of IL-8 is due to the distinct chromatin architecture on the enhancer/promoter before the arrival of the inducing signal. In expressing epithelial cells the enhancer/promoter is nucleosome-free, whereas in non-expressing B cells a nucleosome masks the entire regulatory region. The B-cell-specific nucleosome contains the histone variant macroH2A, which is responsible for preventing transcription factor binding. Recruitment of the repressive macroH2A nucleosome requires direct interactions between ATF-2 bound to the nearby AP1 site and macroH2A and it is regulated by DNA-induced protein allostery. siRNA against ATF-2 or macroH2A rescues IL-8 transcription in B cells. Thus, a transcription factor can work as a transcriptional repressor by orchestrating and maintaining the assembly of specialized local chromatin architectures.
Agelopoulos
Marios
M
Institute of Molecular Biology and Genetics, Biomedical Sciences Research Center 'Al. Fleming', Vari, Athens, Greece.
Thanos
Dimitris
D
D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D004742:Enhancer Elements, Genetic / Q000502:physiology; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C508606:CXCL8 protein, human; D006657:Histones; D016209:Interleukin-8; D009707:Nucleosomes; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C120756:macroH2A histone