The mouse genetic data complements the human and the use of GWAS in HS mice promises to deliver more candidate genes. The challenge will be to test these candidates either in vitro or in vivo. Functionally validated candidates may then be considered as potential therapeutic targets. Papers of particular interest, published within the period of review, have been highlighted as: • of special interest The authors are funded by the Medical Research Council buy PD-0332991 (MRC), UK. “
“Current Opinion in Genetics & Development 2014, 25:8–14 This review comes from a themed issue on Genome architecture and expression Edited by Victor Corces and David L Levens For a complete overview see the

Issue and the Editorial Available online 24th January 2014 0959-437X/$ – see front matter, Published by Elsevier Ltd. http://dx.doi.org/10.1016/j.gde.2013.11.006 In Norse mythology, the trickster Loki plays the role of “Stirrer of strife, mischief-monger, Maker of laughter and bringer of change, Friend and foeman, order and chaos” [1]. Akin to Loki,

tiny, positively charged proteins called histones impose different chromatin states and encode epigenetic changes in an otherwise staid genome. These proteins date back to the dawn of eukaryotic evolution, spanning protozoans, Bcl-2 inhibitor fungi, animals, and plants. Indeed, prokaryal and archaeal species are the earliest genomes known to have evolved histone-like proteins [2 and 3]. Bacterial genomes contain histone-like HU proteins, which bind and bend DNA, stabilize higher order chromosomal folding during replication, and regulate transcription (Figure 1a) [2]. Histone-like proteins are also present in the archaea [3]. For example, in the extremophile Methanothermus fervidus, archaeal histones ( Figure 1b,c) form tetrameric complexes, which wrap

∼70 bp of DNA in a right-handed toroid, into which histone subunits are exchanged in response to environmental stressors such as salt concentration or temperature [ 4]. Another archaeal organism, Cytidine deaminase Methanopyrus kandleri, contains a fused “doublet” histone fold protein, wherein one of the histone folds shares homology with the histone folds of eukaryotic H2A and H4 ( Figure 1d), suggesting that the eukaryotic histone genes for H2A, H2B, H3, and H4 probably arose from duplication of primitive archaeal histone genes [ 5]. In eukaryotes, 147 bp of DNA wrap in a left-handed torus around an octameric complex composed of two copies each of the invariant histones H3, H2A, H2B and H4 (Figure 1e) [6]. Since the discovery that the vast majority (>70%) of DNA in eukaryotes is packaged into nucleosomes, and the landmark X-ray diffraction study by Finch and Klug showing chromatin was organized into highly compacted 30 nm wide solenoidal coils (Figure 1f), histones were proposed to function primarily as packaging material for ever-growing eukaryotic genomes [7].