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Histone Target Selection Within Chromatin: an Exemplary Case of Teamwork

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Histone Target Selection Within Chromatin: an Exemplary Case of Teamwork Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Histone target selection within chromatin: an exemplary case of teamwork Marie-Eve Lalonde, Xue Cheng, and Jacques Coˆ te´ 1 St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Centre de Recherche du CHU de Que´bec-Axe Oncologie, Hoˆ tel-Dieu de Que´bec, Quebec City, Quebec G1R 2J6, Canada Histone modifiers like acetyltransferases, methyltrans- influence chromatin dynamics (Tan et al. 2011; Zentner ferases, and demethylases are critical regulators of most and Henikoff 2013). DNA-based nuclear processes, de facto controlling cell Histone PTMs can be deposited on or removed from cycle progression and cell fate. These enzymes perform chromatin by different enzymes. These ‘‘writers’’ and very precise post-translational modifications on spe- ‘‘erasers’’ of histone marks include different kinases and cific histone residues, which in turn are recognized phosphatases, ubiquitin ligases and deubiquitinases, by different effector modules/proteins. We now have a lysine/arginine methyltransferases, and demethylases. better understanding of how these enzymes exhibit such To date, numerous lysine methyltransferases have been specificity. As they often reside in multisubunit com- identified, and each can either mono-, di-, or trimeth- plexes, they use associated factors to target their sub- ylate and may act on only a specific methylation status strates within chromatin structure and select specific of a residue. Conversely, there are two classes of histone histone mark-bearing nucleosomes. In this review, we lysine demethylases identified: the LSD1 family (found cover the current understanding of how histone modi- only in humans/mammals) and the Jumonjis (Greer and fiers select their histone targets. We also explain how Shi 2012). different experimental approaches can lead to conflict- Lysine acetylation entails the addition of an acetyl ing results about the histone specificity and function of group on histone residues by histone acetyltransferases these enzymes. (HATs) and their removal by histone deacetylases (HDACs). HATs and HDACs were the first modifiers Chromatin is a very dynamic structure, allowing com- isolated, and since then, countless studies have exten- paction of DNA in the cell nuclei. The basic unit of sively described their interactions with chromatin. Not chromatin is the nucleosome, which is composed of an only has characterization of HATs and HDACs been octamer of the four canonical histones (H2A, H2B, H3, very useful to understand their recruitment to chroma- and H4), around which 147 base pairs (bp) of DNA is tin and their specific activity, but they have also served wrapped. Many actors regulate access to the DNA within as a model of how other types of modifiers use similar chromatin, such as ATP-dependent remodeling com- features for their own binding and activity. There are two plexes, histone chaperones, histone variants, and chroma- major classes of HATs: the GNAT (Gcn5 N-acetyltransfer- tin-modifying complexes. Post-translational modifications ase) family and the MYST (Moz, Ybf2 [Sas3], Sas2, and (PTMs) of histones mostly occur on their N-terminal tails. Tip60) family. Other HATs with less clearly conserved They play a major role in the regulation of the chromatin catalytic domains also exist, the most recognized being dynamic by either influencing its higher-order structural CBP/p300. Acetyl marks are removed by three major organization or recruiting different proteins implicated classes of HDACs, classified according to their homology in diverse biological functions. Four major histone modi- with the yeast enzymes Rpd3, Hda1, and NAD-dependent fications have been shown to influence chromatin acces- Sir2/sirtuin (for review, see Steunou et al. 2014). sibility; namely, lysine acetylation, lysine/arginine meth- Histone PTMs can influence chromatin accessibility in ylation, serine/threonine phosphorylation, and lysine two ways. Some modifications have direct impact on its ubiquitination. More recently, new PTMs, including ly- structural organization by affecting nucleosome proper- sine acylation or crotonylation and serine glycosylation, ties or higher-order chromatin structure. Other modifi- have begun to emerge, but little is known about how they cations can also act as docking sites for histone PTM ‘‘readers,’’ which bind chromatin through their histone Ó 2014 Lalonde et al. This article is distributed exclusively by Cold [Keywords: acetyltransferases; methyltransferases; histone-modifying Spring Harbor Laboratory Press for the first six months after the full-issue complexes; histone tails; chromatin readers] publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). 1Corresponding author After six months, it is available under a Creative Commons License E-mail [email protected] (Attribution-NonCommercial 4.0 International), as described at http:// Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.236331.113. creativecommons.org/licenses/by-nc/4.0/. GENES & DEVELOPMENT 28:1029–1041 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/14; www.genesdev.org 1029 Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Lalonde et al. modification recognition domains (Musselman et al. Therefore, a pool of free histones can be isolated in the 2012b). Some of these factors may also alter chromatin nucleoplasm, although the majority is still bound to conformation, and the majority are involved in cellular chromatin. Both conditions can also be recreated in vitro, functions such as DNA replication or repair, cell cycle where free histones and chromatin/nucleosomes may be progression, or transcriptional regulation. Therefore, PTMs used to characterize diverse modifying activities. More- play a major role in controlling various nuclear processes. over, fewer physiological substrates like monomeric A well-balanced homeostasis of the incorporation of these recombinant histone and histone N-terminal synthetic PTMs is thus required for the cells to maintain a tight peptides are also frequently used. These different sub- regulation of cellular pathways. Not only does the de- strates have allowed identification of context-specific position timing play a crucial role, but their genomic activities (Fig. 1A,B). For instance, some enzymes react localization also needs to be highly specific. In fact, many only with nucleosomal histones. The Dot1 methyltrans- diseases have been associated with the misincorporation ferase, which is responsible for the methylation of H3K79 of histone marks. Several other reviews have focused on in yeast, is able to accomplish this only in the context the mechanisms of PTM misregulation leading to disease of chromatin and has no activity on free histones or re- (Chi et al. 2010; Fullgrabe et al. 2011; Smith et al. 2011; combinant H3 (Lacoste et al. 2002; Ng et al. 2002; Dawson and Kouzarides 2012; Shen and Laird 2013; Fingerman et al. 2007). The same is observed in the case Steunou et al. 2014). of Set2 methyltransferase, which methylates H3K36 Most of the chromatin-modifying enzymes have adopted mainly in a chromatin context (Strahl et al. 2002), al- a very ingenious strategy to guarantee such accurate though minor relative Set2 activity has also been reported deposition and specificity of histone PTMs. These cata- on histone tetramers and core histones (Du et al. 2008). In lytic proteins are generally found within large multisub- contrast, some other enzymes are able to acetylate only unit complexes. Many subunits of these complexes con- nonnucleosomal histones. The yeast acetyltransferase tain different histone recognition modules that can bind Rtt109, which is found in complex with the histone chromatin on particular histone marks. Together, they chaperone Vps75, acetylates H3K56 of newly synthesized cooperate to bind and target only specific residues on histones in the nucleoplasm but does not acetylate nucle- chromatin (Yun et al. 2011; Musselman et al. 2012b). osomal H3 (Han et al. 2007). The Asf1 chaperone is also Moreover, some of these complexes also possess more required for Rtt109 to acetylate H3K56 by presenting H3– than one activity. For example, the SAGA complex has H4-associated dimers to the enzyme (Recht et al. 2006; both acetyltransferase (Gcn5) and deubiquitinase (Ubp8) Adkins et al. 2007). Other enzymes can modify both free activities (Ingvarsdottir et al. 2005; Lee et al. 2005), histones and nucleosomes but show clear preferences in while the related ATAC complex possesses two acetyl- vitro, as shown by CBP/p300 acetyltransferase’ s stronger transferases (Gcn5 and Atac2) (Suganuma et al. 2008). activity on free histones compared with chromatin Other complexes, such as TIP60, combine chromatin (Ogryzko et al. 1998; Ito et al. 2000; Deng et al. 2003). remodeling (H2A.Z incorporation by the p400 subunit) Interestingly, some HAT complexes can target both free and modifying activities (acetylation by the Tip60 sub- and nucleosomal histones in vitro but will show differ- unit) (Kusch et al. 2004; Altaf et al. 2009). These large ential specificity for each substrate. The MYST complex complexes are thus multifunctional and can act in differ- HBO1–JADE can acetylate both H3 and H4 on free ent cell processes by achieving various modifications histones but is much more specific for H4 in the context depending on the cellular context. This
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