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Abstract
Histone acetylation, one of the first and best studied histone post-translational modifica - tions (PTMs), as well as the factors involved in its deposition (writers), binding (readers) and removal (erasers), have been shown to act at the heart of regulatory circuits con- trolling essential cellular functions. The identification of a variety of competing histone lysine-modifying acyl groups including propionyl, butyryl, 2-hydroxyisobutyryl, crotonyl, malonyl, succinyl and glutaryl, raises numerous questions on their functional significance, the molecular systems that manage their establishment, removal and interplay with the well-known acetylation-based mechanisms. Detailed and large-scale investigations of two of these new histone PTMs, crotonylation and 2-hydroxyisobutyrylation, along with his- tone acetylation, in the context of male genome programming, where stage-specific gene expression programs are switched on and off in turn, have shed light on their functional contribution to the epigenome for the first time. These initial investigations fired many addi - tional questions, which remain to be explored. This review surveys the major results taken from these two new histone acylations and discusses the new biology that is emerging based on the diversity of histone lysine acylations. Keywords: Spermatogenesis, X Inactivation, HDAC, HAT, Bromodomain Cell Journal(Yakhteh), Vol 17, No 1, Spring 2015, Pages: 1-6 Citation: Rousseaux S, Khochbin S. Histone acylation beyond acetylation: terra incognita in chromatin biology. Cell J. 2015; 17(1): 1-6. Introduction tion (K ) and also that some of the well-known Bu Histone lysine acetylation was the first histone acetyltransferases could be involved in these acylation identified in the sixties and hence it is modifications (3). the first histone post-translational modification These findings represented a turning point in our (PTMs) for which molecular systems, mediating understanding of how histone marks, and more par- its establishment, removal and, later on, its rec - ticularly histone acetylation, could signal chroma- ognition, were discovered and thoroughly inves - tin activities. Indeed, most of the identified histone tigated (1). Histone-deacetylase (HDAC) inhibi - K and K sites are also known to be acetylated tors were also among the first identified small Pr Bu (3, 4). Therefore these studies raised questions on molecules "epigenetic" drugs used to explore the functional similarities and differences between the cellular regulatory circuits involving histone acetylation and these two newly found acylations. acetylation. These inhibitors are now showing However, up to now, there has been no clear an- their efficacy in a series of unrelated pathologies swer to these questions. including cancer (2). The situation became even more complicated Several years ago, a pioneering work report - after a second wave of histone PTM discovery ed the important discovery that histones could published in several recent articles reporting the bear lysine propionylation (K ) and butyryla- Pr CELL JOURNAL(Yakhteh), Vol 17, No 1, Spring 2015 1 Epigenetics through A New Histone Language identification of additional acylated lysine sites Spermatogenesis: an ideal system to assign a including crotonylation (K ), 2-hydroxyisobu- functional significance to unknown histone PTMs Cr tyrylation (K ), succinylation (K ), malonylation Hib Su Spermatogenesis is a specific differentiation (K ) and glutarylation (K ) (4-7). Ma Glu program that aims at producing highly special - ized haploid cells capable of transporting the Since all the newly discovered acylations male genome out of the father’s organism into could potentially compete with histone lysine the female genital track to meet the oocyte (8). acetylation, questions have emerged such as how the choice of histone acylation is made, The requirement for these cells to leave their which enzymes are involved and what the func - organism of production is backed by very spe - tional interplay is between these modifications cific gene expression programs that are mostly in general and more specifically with histone silent in all somatic adult tissues but become acetylation (Fig.1). active only in male germ cells in an orderly manner (9-11). Progenitor adult stem cells, or However, two of these studies, including a de- spermatogonia, continuously feed a flow of tailed genome-wide mapping of histone K and Cr cells, which will undergo meiosis followed by K sites respectively in differentiating mouse Hib a post-meiotic differentiation process. Distinct spermatogenic cells brought the first hints con - and specialized gene expression programs are cerning the functional significance of these new turned on during each of the three major stages histone PTMs relative to the corresponding his- of spermatogenesis, which include self-renew - tone acetylation (4, 5). ing mitotically dividing stem cells (spermatogo - nia), meiotically dividing cells (spermatocytes) and haploid cells (spermatids). The latter cells undergo a complete metamorphosis to become "swimming" mature spermatozoa. Defined cat - egories of genes become in turn active or silent during each of these periods of spermatogen - esis (10). Additionally, there are specific chro - mosome-wide transcriptional regulatory events that make this system a particularly rich one in terms of the variety of gene expression regu - latory events. Indeed, during meiosis, the sex chromosomes become transcriptionally inac - tive, following a phenomenon known as meiotic sex chromosome inactivation (MSCI) while, af - ter meiosis, a fraction of the X/Y-linked genes escapes the inherited general silencing and is reactivated (12, 13). Genome-wide mapping of particular histone Fig.1: Molecular systems orbiting around histone acetylation marks in both meiotic and post-meiotic cells have been the centre of comprehensive investigations leading to the identification and functional characterization of the three associated with whole genome gene expres - major classes of actors involved in generating [acetyltransferases sion profiling, allows assigning a functional (HATs)], reading [bromodomains (BRDs)] and erasing [deacety- significance to a given mark. Indeed, at first, lases (HDACs)] signalling to chromatin based on acetylation. In contrast, our knowledge of the molecular machinery managing like in many other cellular systems, histone signalling through histone acylations other than acetylation is mark distributions are considered as a function very poor and only a few enzymes involved in their establish- ment and removal have been identified so far. All the acyl group of genome annotations: intergenic regions, gene donors are generated through cell metabolism and hence a criti - promoters, enhancers, transcriptional start sites cal question to address is how cell metabolism drives all these (TSS) exons, introns and etc. Once a significant modifications and how it imposes a specific choice on the use of acyl group. association of a given histone PTM with gene Ac; Acetylation, Pr; Propionylation, Bu; Butyrylation, Hib; 2-hy - regulatory elements, such as enhancers, TSS droxyisobutyrylation, Cr; Crotonylation, Su; Succinylation, Glu; Glutarylation and CBP/p300; CREB-binding protein/EP300. and etc, is observed, in a second step, it becomes CELL JOURNAL(Yakhteh), Vol 17, No 1, Spring 2015 2 Rousseaux and Khochbin possible to consider the transcriptional status of revealed a situation somewhat similar to that the corresponding genes. Taking into account described above for histone K . H4K8 was Cr Hib both meiotic and post-meiotic cells with differ - found enriched at the TSS of active genes and ent gene expression profiles, one can easily as - in post-meiotic cells, the presence of H4K8 Hib sociate a particular histone mark with increased at gene TSS appeared to be a better indicator of or decreased gene activities (14). When these transcriptional activity than H4K8 . Interest- Ac studies consider a given histone acylation in ingly, considering X-linked genes, the majority parallel with histone acetylation, it becomes of genes escaping inactivation in post-meiotic possible to monitor the interplay between his - cells, which had been previously identified as tone acylation and acetylation (4, 5, 15). labelled with histone K , were also marked Cr with H4K8 . However, the TSS of these genes Hib Additionally, a unique event during the post- was not associated with H4K8 (5). Ac meiotic phases of spermatogenesis is the al - most genome-wide histone eviction followed Therefore these analyses reveal that the two by repackaging of the genome with small basic newly identified histone acylations, similar to non-histone proteins. Interestingly, it has been histone acetylation, are associated with tran - observed that, in different species, histone re - scriptionally active genes. However, the specif - moval is associated with a genome-wide his - ic situation of post-meiotic genes labelled with tone hyperacetylation. This system constitutes both histone K and K , in particular X-linked Cr Hib another interesting readout for comparisons genes that escape the inherited MSCI, suggests between histone acetylation and other histone a specific role for these acylations that may not acylations (16). be shared by acetylation. Histone crotonylation and 2-hydroxyisobutyryla- Hot topics on the functional significance of his - tion: two specific histone marks indicating active tone acylations genes Detailed study of the two newly discovered The genome-wide mapping of histone ly - histone acylations, K and K , suggests that, Cr Hib sine K in differentiating spermatogenic cells although both could mark active genes in a Cr shows an enrichment of this mark at gene TSSs. similar way as K , they might also act under Ac Interestingly, a specific category of male germ specific circumstances, where histone acetyla - cell-specific genes is associated with an in - tion would not function properly. In support of crease in histone crotonylation between meiotic this hypothesis one could consider the existence and post-meiotic stages. Further investigations of enzymes involved in their establishment and have revealed that they are genes, which be - removal that are different from those mediating come active after meiosis and are specifically histone acetylation. The above reported inves - expressed in haploid male germ cells. Among tigations have indeed shown that histone cro - these late activated genes, of particular inter - tonylation behaves differently from acetylation est are the X-linked genes (localised on the X with respect to class I and II HDACs, which chromosome) for which this increase in histone are efficient deacetylases but poor decroto - crotonylation precisely marks genes that escape nylases (4). Additional investigations revealed inactivation. Under the same conditions, no par - that HDAC3 (18) and Sirt1 and Sirt2 (19) could ticular association was observed between varia - decrotonylate histone peptides in vitro to some tions in lysine acetylation (K ) and changes in extent. A new study, including in vivo assays, Ac gene expression (4). Later on, an independent showed that Sirt3 is the major in vivo decro- study confirmed the above reported finding and tonylase, specifically involved in the regula - tion of H3K4 (20). Sirt3 being essentially a further demonstrated that histone crotonylation Cr mitochondrial enzyme, the remaining question specifically marks X-linked genes that escape is to what extend the residual amounts of non- inactivation (17). mitochondrial enzyme could regulate chromatin Similar genome-wide analyses were per - crotonylation. formed to explore histone K , but this time Hib on a specific lysine site of histone H4, K8, and Regarding K , a previous work showed that, Hib CELL JOURNAL(Yakhteh), Vol 17, No 1, Spring 2015 Epigenetics through A New Histone Language when this mark is present on free histones, it could characterization of class I/II HDACs and Sir - be erased in vitro by HDAC1, 2 and 3 (5). How- tuins involved in its removal. ever, the efficiency of these reactions compared to Another interesting question concerns enzymes deacetylation by the same enzymes and whether involved in the establishment of histone acyla- they could take place in vivo remain to be inves- tion. With this regard, we have limited knowledge. tigated. The only available information is that the histone There is also information on another lysine acetyltransferases (HATs) CREB-binding protein/ acylation, K , which shows resistance to all EP300 (CBP/p300) can mediate histone propio- Glu HDACs except Sirt5 (6). nylation and butyrylation (3). Also these enzymes probably catalyse the establishment of additional A particular characteristic of post-meiotic sper- acyl groups such as succinyl and glutaryl (6). The matogenic cells is that, prior to histone eviction, questions are whether these enzymes catalyse oth- they undergo a genome-wide transcriptional re- er actylations and also whether other known HATs pression (21, 22). This could be associated with would be capable of mediating these modifica - a gradual instauration of a general transcriptional tions. repressive environment and a need for the genes that remain active in these cells to use "stronger" As discussed above, the knowledge of the mo- active histone marks, meaning histone PTMs that lecular systems controlling the establishment and would be more stable and would better resist an removal of histone acylations beyond acetylation enzymatic removal by at least some of the com- could represent an essential step for a better un- mon deacetylases. derstanding of the functional significance of these new marks. Although at the genomic scale the presence of such an epigenetically-driven repressive en - The answer to this question leads to another vironment has not been clearly established in question: if the same enzymes mediate multiple early post-meiotic spermatogenic cells, at the histone acylations, what drives the choice on the sex chromosomes scale, there is no doubt about acyl group to be transferred? the existence of a repressive environment. First, If a particular HAT catalyses several distinct acyla- most of the sex chromosome-linked genes in - tions, then the availability of the donor acyl group activated during meiosis remain silent in post- should influence the outcome of the reaction. meiotic cells and second, sex chromosomes lo - cate adjacent to the repressive heterochromatic Indeed, it is believed that Co-enzyme A is the chromocenter (15). Therefore, it is possible to carrier and donor of most of the acyl groups (4, speculate that in such an environment acyla - 5, 23-25). Since Acyl-CoAs are generated follow- tions other than acetylation could be required to ing different metabolic pathways, their availability overcome and resist gene silencing. should directly depend on the state of cell metabo- lism, which should in turn have influence on the Indeed, in many cases, class I and II HDACs nature of the acyl groups used to modify histones contribute to gene silencing, mostly by deacet - (Fig.1). ylating chromatin. Interestingly, as mentioned above, histone K and K are not good sub - Cr Glu Conclusion strates for class I and II HDACs and need the class III enzymes, more specifically Sirt3 and The recent breakthrough discovery of a large Sirt5, to be removed (6, 20). As a consequence, panel of new histone PTMs should definitely since all HDACs contribute to the instauration change our vision of the epigenome. Indeed, of a repressive chromatin, histone crotonylation about twenty years of gradually intensifying re - as well as glutarylation offer a better chance search on acetylation and thousands of publica - to resist repression than histone acetylation, a tions were dedicated to only one of the many mark that could be removed by all these en - possible histone lysine acylations. Now the zymes. The same reasoning could apply for his - question is whether all the discoveries about the tone K . However, in this case, a strong con - molecular signalling relying on histone acetyla - Hib clusion on this mark’s stability awaits a better tion could also stand and apply if another acyl CELL JOURNAL(Yakhteh), Vol 17, No 1, Spring 2015 4 Rousseaux and Khochbin Lysine succinylation and lysine malonylation in his - group replaces the acetyl. The next question is tones. Mol Cell Proteomics. 2012; 11(5): 100-107. whether specific signalling to chromatin de - 8. Hess RA, de Franca LR. 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Cell Journal (Yakhteh) – Pubmed Central
Published: Apr 8, 2015