Review The transcriptional code of human IFN-β gene expression Ethan Ford, Dimitris Thanos ⁎ Institute of Molecular Biology, Genetics and Biotechnology, Biomedical Research Foundation, Academy of Athens, 4 Soranou Efesiou Street, Athens 11527, Greece abstract article info Article history: Received 4 June 2009 Received in revised form 15 January 2010 Accepted 20 January 2010 Available online 30 January 2010 Keywords: Chromatin Transcription Enhanceosome Interferon-β NF-κB IRF-3 Activation of interferon-β transcription is a highly ordered process beginning with the delivery of NF-κB to the IFN-β enhancer through a process involving stochastic interchromosomal interactions between the IFN-β enhancer and specialized Alu elements. NF-κB delivery is followed by the binding of ATF-2/c-Jun and IRF proteins in a highly cooperative fashion. The assembled “enhanceosome” then recruits PCAF/GCN5 which acetylates the histone tails of the adjacent nucleosomes. The transcriptional coactivator CBP, which binds in a complex with the RNA polymerase II holoenzyme is recruited by the enhanceosome replacing PCAF/GCN5. Next, SWI/SNF, which is part of the holoenzyme complex, induces a conformational change in a nucleosome positioned over the transcriptional start site allowing TFIID to bind, which promotes the sliding of this nucleosome to a new downstream position. At this point the full pre-initiation complex is assembled and transcription commences. This detailed picture of the IFN-β transcription program gathered through years of rigorous studies, now serves as a paradigm for understanding complex transcriptional switches in eukaryotic systems. © 2010 Elsevier B.V. All rights reserved. 1. Introduction Understanding how the cell translates the transcriptional code contained within the cis-acting regulatory sequences of genes into the complex pattern of gene expression of higher eukaryotes is one of the major challenges of modern biology. The central question in under- standing this process is to explain how a limited number of transcription factors, often with promiscuous DNA binding specificities, direct the tightly controlled gene expression profile of the cell [1]. Different developmental and external stimuli often activate several of the same transcription factors, yet cause a completely different transcriptional response. For example, the NF-κΒ family of transcription factors responds to a wide variety of developmental and external stimuli [2]. There are hundreds of genes that are regulated by NF-κΒ, yet each inductive queue that activates NF-κΒ leads to distinct transcriptional responses [3]. Genetic information is stored in chromatin, a highly compacted structure. Thus, a key question is how various regulatory proteins gain access to their DNA binding sites to control DNA mediated processes like transcription, replication, recombination, etc. The spatial arrangement of the chromatin fiber and the genome as a whole dramatically affects the function of DNA [4,5]. Thus, knowing the DNA sequence and the identity of the factors required for the expression of any given gene is insufficient to understand how a gene is regulated. Nucleosomes are the basic unit of eukaryotic chromatin, consisting of a histone octamer core around which 147 bp of DNA is wrapped. Each histone core is composed of two copies of each of the histone proteins H2A, H2B, H3 and H4. The amino-terminal histone tails extend from the core structure and are subject to covalent modifica- tions such as acetylation, phosphorylation and methylation. These modifications are carried out by enzymes recruited to chromatin by transcriptional regulatory proteins and mark the underlying genes for transcriptional activation or repression [6]. Histone modifications can influence nucleosome stability and they provide a layer of information in addition to the DNA sequence for the recruitment of additional transcriptional regulatory proteins. Modification of histones at one amino acid position can influence the type of modifications at other positions. An additional way to mark genes for activation or repression of transcription is by replacing canonical histones (mainly H2A and H3) with histone variants (mainly H2A.Z, H3.3 and macroH2A) at selected nucleosomes [7]. Histone variants such as H2A.Z and H3.3 are found in association with active genes and/or genes poised for transcriptional activation, whereas macroH2A is enriched in repressed genes. Until recently, it was unknown whether nucleosome positioning on DNA is random or the nucleosomes reside at specific locations. Random nucleosome positioning in chromatin would simply package DNA, and the transcriptional machinery would deal with it as an obstacle to be removed or relaxed for transcription to occur. Alternatively, the strategic positioning of nucleosomes on selected genes could play a true regulatory role in controlling gene expres- sion [8]. More specifically, the phasing, rotational and translational setting of a given nucleosome would preferentially allow the binding of selected proteins to the underlying DNA sequence, thus working as a gatekeeper in accessing the DNA code. It is now clear that the Biochimica et Biophysica Acta 1799 (2010) 328–336 ⁎ Corresponding author. Tel.: + 30 210 6597244; fax: + 30 210 6597599. E-mail address: thanos@bioacademy.gr (D. Thanos). 1874-9399/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagrm.2010.01.010 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagrm