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Synthetic Histone Code Available online at www.sciencedirect.com ScienceDirect Synthetic histone code 1 2 3 Wolfgang Fischle , Henning D Mootz and Dirk Schwarzer Chromatin is the universal template of genetic information in all copies each of the core histones H2A, H2B, H3, and H4 eukaryotic cells. This complex of DNA and histone proteins not and one copy of linker histone H1, Figure 1a) [1]. By only packages and organizes genomes but also regulates gene various levels of folding, the originating primary chroma- expression. A multitude of posttranslational histone tin fiber can be organized into various structural arrange- modifications and their combinations are thought to constitute ments, including highly condensed mitotic chromosomes a code for directing distinct structural and functional states of (Figure 1b). While the basic architecture of nucleosomes chromatin. Methods of protein chemistry, including protein is the same throughout the genome, posttranslational semisynthesis, amber suppression technology, and cysteine modifications (PTMs) of histones are central means of bioconjugation, have enabled the generation of so-called increasing the biochemical divergence that regulates designer chromatin containing histones in defined and chromatin structure and function [2,3]. Histone PTMs homogeneous modification states. Several of these are structurally diverse and include methylation, acetyla- approaches have matured from proof-of-concept studies into tion and ubiquitinylation of lysine, as well as phosphor- efficient tools and technologies for studying the biochemistry of ylation of serine and threonine residues (Figure 1c). More chromatin regulation and for interrogating the histone code. We than 150 histone modification sites have been identified summarize pioneering experiments and recent developments in different experimental systems. Major sites of modifi- in this exciting field of chemical biology. cation cluster within the unstructured regions of the N- Addresses terminal histone tails that vary between 10 and 35 amino 1 Max Planck Institute for Biophysical Chemistry, 37077 Go¨ ttingen, acids in length. These are protruding out from the nucle- Germany osome core (Figure 1a). 2 Institute of Biochemistry, University of Muenster, 48149 Muenster, Germany 3 Research over the past years has focused on defining the Interfaculty Institute of Biochemistry, University of Tu¨ bingen, 72076 Tu¨ bingen, Germany distribution, biochemistry and cellular function of individ- ual and combinations of histone marks. A ‘histone code’ Corresponding authors: Fischle, Wolfgang (wfi[email protected]), Mootz, hypothesis has been put forward that defines chromatin as Henning D ([email protected]) and Schwarzer, Dirk ([email protected]) dynamic programming platform, which integrates internal and external cellular signals [2,3]. Histone modifying enzymes are considered the writers of the histone code. Current Opinion in Chemical Biology 2015, 28:131–140 Chromatin factors possessing PTM-binding domains serve This review comes from a themed issue on Synthetic biomolecules as histone code readers and execute regulatory functions upon recruitment. Finally, dedicated PTM-removing Edited by Christian Hackenberger and Peng Chen enzymes are the erasers of histone PTMs [4–7]. For a complete overview see the Issue and the Editorial Available online 6th August 2015 Deciphering the complex cross-talk between histone http://dx.doi.org/10.1016/j.cbpa.2015.07.005 PTMs, chromatin factors and gene regulation is a major 1367-5931/# 2015 Elsevier Ltd. All rights reserved. research challenge [8]. While the accessibility of ‘designer chromatin’ composed of histones with defined and ho- mogeneous modification states has been a central bottle- neck in chromatin research, novel chemical approaches are providing powerful tools enabling important discov- eries of the rules of the histone code [4–7,9–12]. Chromatin and posttranslational histone modifications Tools for designer chromatin The physiological template of genetic information in all Chromatin research has benefitted strongly from peptide eukaryotic cells is chromatin, the complex of DNA and chemistry. Especially, the availability of building blocks histone proteins. As signaling platform, chromatin inte- of modified amino acids has enabled the synthesis of grates a variety of internal and external cellular inputs. histone peptides with defined modification patterns. These direct distinct local and global structural and Such histone-derived peptides have been instrumental functional states of chromatin, thereby controlling gene for many key discoveries on the readers, writers and expression [1]. eraser of histone PTMs. However, histone-peptides can only recapitulate a minor fraction of the complex In the repeating unit of chromatin, the nucleosome, DNA chromatin structure (Figure 1). Consequently, major is wrapped around an octamer of histone proteins (two efforts have been untertaken to site-specifically introduce www.sciencedirect.com Current Opinion in Chemical Biology 2015, 28:131–140 132 Synthetic biomolecules Figure 1 (a) (c) nucleosome CH3 O H3C O NH 1-3 ⊕ NH NH 0-2 N N N H H H O O O acetyl-lysine methyl-lysine ubiquitin-lysine (Kac) (Kme) (Kub) histone tail O O O P O O P O O O CH3 N N H H O O phospho-serine phospho-threonine (Sph) (Tph) (b) condensation into higher order DNA nucleosomes chromatin structures Current Opinion in Chemical Biology Histones, nucleosomes and chromatin. (a) Structure of the nucleosome core particle. Histones are color-coded as follows: H2A: yellow, H2B: red, H3: blue, H4: green. The illustration was generated from pdb file: 1KX5. (b) Packaging of DNA into nucleosomes and chromosomes. Intermediate packaging stages are not illustrated. (c) Selected posttranslational modifications of histones including acetylation, methylation and ubiquitination of lysine as well as phosphorylation of serine and threonine residues. modification marks into full-length histones, nucleo- 2-chloro-ethyl-methylammonium or bromo-ethyl- somes, arrays of nucleosomes and even into chromatin methylammonium compounds (1) the respective meth- of living cells. These approaches draw from the techno- yl-thialysine (2) residues were generated in high yields logical repertoire of modern protein chemistry [4–7]. (Figure 2a). Downstream experiments showed that these so-called methyl-lysine analogs (MLAs) mim- Selective modification of cysteine residues icked properties of methylated lysine in peptide and The most widely used strategy for generating modified nucleosomal context by recruiting chromatin readers. histones is the selective conversion of cysteine residues into mimics of modified amino acids. The chemical In a similar fashion methyl-arginine analogs (4) were properties of the cysteine thiol group are unique among generated [14]. In this case a,b-unsaturated amidines the proteinogenic amino acids. Selective alkylation of (3) served as alkylation agents. Extending this approach this soft nucleophile has been used in traditional bio- to acetyl-thialysine (6) turned out much more challenging chemistry and this approach has recently experienced a [15]. The treatment of cysteine with 2-bromoethyl-acet- renaissance for site-specific introduction of mimics of ylamine (5) or with more reactive N-acetyl-aziridine, were PTMs. Since natural cysteine residues are absent in core either poor yielding or led to undesired side-products. histones with exception of a single residue in H3, this Alkylation with methylthiocarbonyl-aziridine (7) con- method is particularly attractive for chromatin chemis- verted cysteine residues into methylthiocarbonyl-thialy- try. In a pioneering report site-directed mutagenesis sine (8), which mimicked some aspects of acetylated was used to introduce cysteine at sites of methylated lysine [15]. Efficient formation of acetyl-thiaLys (6) lysine residues in otherwise Cys-free mutant histone was finally achieved with N-vinyl-acetamidine (9), how- H3 as well as histone H4 [13]. Upon treatment with ever not by direct conjugation but via the radical thiol-ene Current Opinion in Chemical Biology 2015, 28:131–140 www.sciencedirect.com Synthetic histone code Fischle, Mootz and Schwarzer 133 Figure 2 (a) O H N N HN (7) SMe HN O X CH3 S + CH3 (1) S N 1-3 N SMe O (2) 1-3 –HX (8) H0-2 O H O NH X = Cl, Br CH 3 HS N CH3 + (3) N H NH2 H (9) O HN CH HN S 3 ν S N N h* , initiator N CH (4) H H (6) 3 O H O O H N CH X 3 (5) cysteine residue O HS R O engineered into (11) HN HN HN S S recombinant histone R –“H2S” N CH3 O O (6) H O (10) (b) – O O O O N + NH N H 3 H recombinant expression recombinant histone Nε-acetyl-lysine with Kac-RS/tRNA containing acetyl-lysine (c) – O – O P O O – – O O O – – O P O O P O H N O HS 2 S SH O O O H H H H N N N H N N 2 S–R H N 2 + 2 H2N N –R–SH H O O O synthetic modified recombinant truncated N-terminal tail peptide histone with N-terminal thiol-thioester semisynthetic histone thioester cysteine residue exchange with modified N-terminal tail (d) ligation 12 + Ub-thioester (NCL) site cleavage of auxiliary O SH HN H HN O N HN N NH2 O (12) H O (13) N NO2 SH O H ligation 13 + Ub-thioester (NCL) photo-cleavable RO site thiol auxiliary OR’ desulfurization Current Opinion in Chemical Biology Chemical approaches for the generation of histones possessing defined modification patterns. (a) Modification of cysteine residues engineered into recombinant histones can be modified into mimics of amino acids carrying posttranslational modifications. (b) Recombinant modified histones are accessible by amber suppression technology. (c) Protein semisynthesis, here: native chemical ligation, affords homogenously modified histones by ligation of synthetic peptide-thioesters and globular folds of histones that possess an N-terminal cysteine residue. (d) Approaches for site-specific ubiquitination of lysine residues by NCL using thiol auxiliaries and d-mercaptolysine. Both approaches can be traceless when the auxiliary is removed by UV irradiation or when the thiol is desulfurized. www.sciencedirect.com Current Opinion in Chemical Biology 2015, 28:131–140 134 Synthetic biomolecules reaction [16].
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