Chatting histone modifications in mammals

B RIEFINGS IN FUNC TIONAL GENOMICS . VOL 9. NO 6. 429^ 443 doi:10.1093/bfgp/elq024 Chatting histone modifications in mammals Annalisa Izzo and Robert Schneider Abstract Keywords: histone modifications; histone methylation; cross-talk; epigenetic; chromatin INTRODUCTION In mammals the genomic information is organized into chromatin. The structural and functional unit of chromatin is the nucleosome, that consists of an octamer of the core histones H2A, H2B, H3 and H4 around which 147 bp of DNA are wrapped [1]. In addition, the linker histone H1 binds the DNA entering and exiting the nucleosome and protects the linker DNA, further compacting chromatin. Chromatin is not a static structure, but in order to allow vital cellular processes to occur, it needs to be dynamically modulated. Three main mechanisms have been proposed to regulate chromatin compaction and decompaction. First, chromatin remodeling complexes use the energy liberated from ATP hydrolysis to actively move and reposition nucleosomes along the DNA [2]. Second, histone variants are incorporated at specific locations where they define a precise chromatin state [3] and third, covalent modifications of histones or DNA can be key to regulation of chromatin structure and all DNA dependent processes [4, 5]. So far the best studied histone modifications are located within the flexible N-terminal tail of the core histones. With the recent improvement of the sensitivity of mass-spectrometrical techniques, new, previously uncharacterized modifications have been identified in vivo both in the tails and in the core domain of histones [6–10]. However, for many histone modifications their functional role is not yet fully understood. HOW DO HISTONE MODIFICATIONS WORK? There are two main mechanisms explaining the impact of histone modifications on chromatin functions. The first is the disruption of contacts between adjacent nucleosomes or between histones and DNA e.g. by charge changes. The best example for this is histone lysine acetylation. Due to its capacity to neutralize the positive charge of lysines, histone acetylation can weaken the affinity between histone Corresponding author. Robert Schneider, MPI for Immunobiology, Stübeweg 51, 79108 Freiburg, Germany. Tel: 0049-0761-51080; Fax: 0049-0761-5108-220; E-mail: Annalisa Izzo, PhD is a postdoctoral scientist at the Max Planck Institute for Immunobiology in Freiburg, where her research focus is the functional role of human H1 in chromatin. Robert Schneider, PhD is a group leader at the Max Planck Institute for Immunobiology in Freiburg. His scientific interests include histone modifications, histone variants and epigenetic regulation of chromatin dependent processes. ß The Author 2011. Published by Oxford University Press. All rights reserved. For permissions, please email: Eukaryotic chromatin can be highly dynamic and can continuously exchange between an open transcriptionally active conformation and a compacted silenced one. Post-translational modifications of histones have a pivotal role in regulating chromatin states, thus influencing all chromatin dependent processes. Methylation is currently one of the best characterized histone modification and occurs on arginine and lysine residues. Histone methylation can regulate other modifications (e.g. acetylation, phosphorylation and ubiquitination) in order to define a precise functional chromatin environment. In this review we focus on histone methylation and demethylation, as well as on the enzymes responsible for setting these marks. In particular we are describing novel concepts on the interdependence of histone modifications marks and discussing the molecular mechanisms governing this cross-talks. 430 Izzo and Schneider LYSINE METHYLATION AND DEMETHYLATION Methylation can occur at different aminoacid residues such as lysine, arginine and histidine. Methylation of lysines and arginines has been extensively studied and implicated in multiple cellular processes [4]. Histone methylation is so far the most complex modification, since its function depends on the precise methylation site and the degree of modification. Lysine residues can be mono-, di- or tri-methylated, whereas arginines can be mono- or di-methylated. In addition arginines can be symmetrically or asymmetrically di-methyleted. Therefore we will focus here on histone methylation and in particular on its complex cross-talk with other modifications. Site and state-specific lysine methylation of histones is catalyzed by a group of lysine methyltransferases (KMT) containing the evolutionarily conserved SET domain [Su(var), enhancer of zeste, Tritorax] (Table 1). They have been sub-grouped into seven main families, named according to their founding member: SUV39, SET1, SET2, EZ, RIZ, SMYD and SUV4-20 [22]. In addition few orphan members have been identified: SET7/9 and SET8 (also known as PRSET7). Proteins within the same family share high similarity within the SET domain as well as in the surrounding sequences [22]. To date the only identified non-SET domain-containing lysine KMTase is DOT1, specific for H3K79 methylation in the core region of H3 [23, 24]. So far methylatiopn of five residues within the N-terminal tail (H3K4, H3K9, H3K27, H3K36 and H4K20) of histones H3 and H4, and of two residues in the globular domain (H3K64 and H3K79) of histone H3 have been functionally characterized. In addition, the linker histone H1 can also be methylated at H1.4K26. In general, H3K9, H3K27 H3K64 H4K20 and H1.4K26 methylation have been implicated in transcriptional silencing [25] whereas, H3K4, H3K36 and H3K79 methylation are associated with transcriptionally active regions [25]. However, depending on the methylation states and the genomic location the same modification might have different functional outcomes. H3K9 methylation is involved in euchromatic gene silencing as well as in heterocromatin formation [26, 27]. H3K27 methylation has an important role in the repression of HOX genes during development and in X chromosome inactivation and imprinting [28–30]. More recently H3K64me3 has been shown by our lab to be enriched at pericentric heterochromatin and to be associated with repeat sequences and transcriptionally inactive genomic regions [31]. In the case of H4K20 each methylation state is implicated in different biological processes. H4K20me1 peaks in M phase and is involved in cell-cycle progression and chromosome condensation [32–34]. Outside of mitosis H4K20me1 is a and DNA, thus creating a more accessible and open chromatin state [11]. In line with these findings, the development of a strategy to produce recombinant nucleosomes fully modified at a specific site showed that histone H4 lysine 16 (H4K16) acetylation inhibits the formation of the condensed 30 nm fiber and the establishment of higher order of chromatin structure [12]. The second mechanism to regulate chromatin dynamics is the recruitment of specific binding proteins by histone (...truncated)