Does chromatin function as a metabolite reservoir?

Abstract

Alternative histone acylations integrate gene expression with cellular metabolic states. Recent measurements of cellular acyl-coenzyme A (acyl-CoA) pools highlight the potential that histone post-translational modifications (PTMs) contribute directly to the regulation of metabolite pools. A metabolite-centric view throws new light onto roles and evolution of histone PTMs. Alternative histone acylations integrate gene expression with cellular metabolic states. Recent measurements of cellular acyl-coenzyme A (acyl-CoA) pools highlight the potential that histone post-translational modifications (PTMs) contribute directly to the regulation of metabolite pools. A metabolite-centric view throws new light onto roles and evolution of histone PTMs. Nuclear genomes are organised by nucleosomes composed of the histone core around which the DNA winds in almost two turns (Figure 1). Chromatin organisation and function, such as gene regulation, is controlled by a multitude of histone PTMs that mostly occur on histone tails protruding from the nucleosomes (N-terminal for all histones and C-terminal for H1, H2A, and H2B) [1.Nitsch S. et al.Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism.EMBO Rep. 2021; 22e52774Crossref Scopus (19) Google Scholar]. Histone PTMs control chromatin structure by changing the charge of histones affecting interaction with DNA (e.g., acetylation) and by creating binding sites for chromatin remodelling factors [1.Nitsch S. et al.Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism.EMBO Rep. 2021; 22e52774Crossref Scopus (19) Google Scholar]. Research of the past decade has underscored the close link between histone PTMs and cellular metabolic states [1.Nitsch S. et al.Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism.EMBO Rep. 2021; 22e52774Crossref Scopus (19) Google Scholar, 2.Ye C. Tu B.P. Sink into the epigenome: histones as repositories that influence cellular metabolism.Trends Endocrinol. Metab. 2018; 29: 626-637Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 3.Trefely S. et al.Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.Mol. Metab. 2020; 38100941Crossref PubMed Scopus (56) Google Scholar]. As histones are some of the most abundant cellular proteins and are highly modified, they have the potential to serve as a reservoir for metabolites such as short chain carboxylic acids like acetate through histone modifications [2.Ye C. Tu B.P. Sink into the epigenome: histones as repositories that influence cellular metabolism.Trends Endocrinol. Metab. 2018; 29: 626-637Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] (Figure 1). Here, we discuss observations consistent with the idea that chromatin serves as metabolite reservoir, namely: (i) new insights into alternative histone acylations and cellular acyl-CoA levels; (ii) the important role of histone deacetylation in cellular states related to nutrient deprivation; and (iii) chromatin acetylation in prokaryotes. Acyl-CoAs, composed of an acyl group (such a acetyl) linked by a thioester bond to cofactor coenzyme A, are critical for acyl transfer in lipid and amino acid synthesis and degradation, glycolysis, and the tricarboxylic acid cycle [2.Ye C. Tu B.P. Sink into the epigenome: histones as repositories that influence cellular metabolism.Trends Endocrinol. Metab. 2018; 29: 626-637Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 3.Trefely S. et al.Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.Mol. Metab. 2020; 38100941Crossref PubMed Scopus (56) Google Scholar, 4.Trefely S. et al.Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.Mol. Cell. 2021; 82: 447-462.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, 5.Jones A.E. et al.A single LC-MS/MS analysis to quantify CoA biosynthetic intermediates and short-chain acyl CoAs.Metabolites. 2021; 11: 468Crossref PubMed Scopus (2) Google Scholar]. As acyl donors, acyl-CoA molecules have the potential to exert signalling functions through PTMs of proteins, especially histones, leading to acetylation, propionylation, and crotonylation, among many others [1.Nitsch S. et al.Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism.EMBO Rep. 2021; 22e52774Crossref Scopus (19) Google Scholar,3.Trefely S. et al.Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.Mol. Metab. 2020; 38100941Crossref PubMed Scopus (56) Google Scholar] (Figure 1). The metabolism of acyl-CoAs is compartmentalised and enzymes that produce various acyl-CoA metabolites are also present in the nucleus, highlighting the role of acyl-CoA in connecting cell metabolism to chromatin regulation (reviewed in [3.Trefely S. et al.Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.Mol. Metab. 2020; 38100941Crossref PubMed Scopus (56) Google Scholar], see [6.Mendoza M. et al.Enzymatic transfer of acetate on histones from lysine reservoir sites to lysine activating sites.Sci. Adv. 2022; 8: eabj5688Crossref PubMed Scopus (2) Google Scholar] as an example). Histone acylations are closely linked to the metabolic state of cells as the Michaelis constant KM of acyl transferases for acyl-CoAs are in the range of the acyl-CoA cellular concentrations. Therefore, there is a correlation between concentrations of different acyl-CoAs and the global abundance of their respective histone acylation with ensuing changes in gene expression [1.Nitsch S. et al.Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism.EMBO Rep. 2021; 22e52774Crossref Scopus (19) Google Scholar,3.Trefely S. et al.Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.Mol. Metab. 2020; 38100941Crossref PubMed Scopus (56) Google Scholar]. For example, the analysis of the yeast metabolic cycle (YMC) illustrates how alternative histone acylations, acetylation, or crotonylation at lysine 9 of histone H3, link cellular metabolism to gene regulation [7.Gowans G.J. et al.Recognition of histone crotonylation by Taf14 links metabolic state to gene expression.Mol. Cell. 2019; 76: 909-921.e3Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. In the YMC, cyclical alterations between high oxygen and low oxygen consumption (LOC) are mirrored by cyclical global changes in histone crotonylation versus acetylation, with histone crotonylation promoted by fatty acid metabolism (which generates crotonyl-CoA) at the LOC stage [7.Gowans G.J. et al.Recognition of histone crotonylation by Taf14 links metabolic state to gene expression.Mol. Cell. 2019; 76: 909-921.e3Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar]. Another example illustrating the axis between specific histone acylation and metabolism was uncovered using metabolite quantitation by liquid chromatography–mass spectrometry [4.Trefely S. et al.Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.Mol. Cell. 2021; 82: 447-462.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar]. Here, the authors demonstrated that nuclear propionyl-CoA derives from isoleucine catabolism and promotes histone propionylation, a mark linked to active gene expression at specific histone lysine residues. Histone acetylation and other histone acylations are dynamic with half-lives of the order of minutes and deac(et)ylation generates short chain carboxylic acids, such as acetate. The acetate can then be converted back to acetyl-CoA (Figure 2), and this holds true also for many other acyl groups [2.Ye C. Tu B.P. Sink into the epigenome: histones as repositories that influence cellular metabolism.Trends Endocrinol. Metab. 2018; 29: 626-637Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,3.Trefely S. et al.Compartmentalised acyl-CoA metabolism and roles in chromatin regulation.Mol. Metab. 2020; 38100941Crossref PubMed Scopus (56) Google Scholar]. Thus, chromatin can be rapidly loaded and unloaded with acyl groups. Progress in accurately measuring subcellular acyl-CoA pools allows one to gauge how these compare to the number of modifiable lysine residues on histones [4.Trefely S. et al.Quantitative subcellular acyl-CoA analysis reveals distinct nuclear metabolism and isoleucine-dependent histone propionylation.Mol. Cell. 2021; 82: 447-462.e6Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar,5.Jones A.E. et al.A single LC-MS/MS analysis to quantify CoA biosynthetic intermediates and short-chain acyl CoAs.Metabolites. 2021; 11: 468Crossref PubMed Scopus (2) Google Scholar]. This indicates that the number of acetate molecules that could be released from chromatin potentially exceeds the number of acetyl-CoA molecules in the cell by orders of magnitude at a given time (Figure 1). Thus, histone acetylation has the potential to act as an acetate reservoir, where the acetate can be released by deacetylases, for example, on starvation, to regenerate acetyl-CoA for energy production and anabolism [2.Ye C. Tu B.P. Sink into the epigenome: histones as repositories that influence cellular metabolism.Trends Endocrinol. Metab. 2018; 29: 626-637Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar] (Figure 2). Furthermore, recent papers provide evidence that acetate from histones released by histone deacetylases can be recycled for histone modifications of other loci and other histone lysine residues on metabolic shifts, which in turn, is connected to changes in gene expression [6.Mendoza M. et al.Enzymatic transfer of acetate on histones from lysine reservoir sites to lysine activating sites.Sci. Adv. 2022; 8: eabj5688Crossref PubMed Scopus (2) Google Scholar,8.Hsieh W.-C. et al.Glucose starvation induces a switch in the histone acetylome for activation of gluconeogenic and fat metabolism genes.Mol. Cell. 2022; 82: 60-74.e5Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar]. The recycling of acyl moieties potentially holds true for alternative histone acylations, such as propionylation or crotonylation. Therefore, one would expect that global histone acetylation drops on starvation and that histone deacetylases are important for viability during starvation. Studies on quiescence in yeast indicate that these predictions hold true. Quiescence is a reversible metabolic state in which cells temporarily abandon the cell cycle, exhibit a decrease in cell size, and shut down transcription and translation of proteins, all leading to greater stress resistance. Several models show that changes in histone PTMs occur with quiescence and are linked to a more compacted chromatin state [9.Bonitto K. et al.Is there a histone code for cellular quiescence?.Front. Cell Dev. Biol. 2021; 9739780Crossref PubMed Scopus (2) Google Scholar]. The McKnight et al. analysis of chromatin changes in budding yeast Saccharomyces cerevisiae during the transition to quiescence highlights the importance of histone deacetylation in this process [10.McKnight J.N. et al.Global promoter targeting of a conserved lysine deacetylase for transcriptional shutoff during quiescence entry.Mol. Cell. 2015; 59: 732-743Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. There are two distinct phases in budding yeast transition from growth phase to quiescence after consumption of the medium’s glucose. The first phase called diauxic shift consists of the stress response and shutdown of the transcriptional machinery in response to carbon source limitation, and the second phase, quiescence itself, consists of loss of global histone acetylation and increase in occupation of promoter regions by nucleosomes. The quiescence process depends on the highly conserved Rpd3 histone deacetylase: in the diauxic shift, Rpd3 targets genes related to ribosome biosynthesis and function; during quiescence, it represses about half of the known genes of S. cerevisiae [10.McKnight J.N. et al.Global promoter targeting of a conserved lysine deacetylase for transcriptional shutoff during quiescence entry.Mol. Cell. 2015; 59: 732-743Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. As a consequence of Rpd3 function, an overall dramatic reduction in histone acetylation occurs after entry into the quiescence state and mRNA levels decrease 30-fold relative to logarithmic growth [10.McKnight J.N. et al.Global promoter targeting of a conserved lysine deacetylase for transcriptional shutoff during quiescence entry.Mol. Cell. 2015; 59: 732-743Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. Remarkably, deletion of RPD3 leads to a significant loss of viability of the cells entering quiescence [10.McKnight J.N. et al.Global promoter targeting of a conserved lysine deacetylase for transcriptional shutoff during quiescence entry.Mol. Cell. 2015; 59: 732-743Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar]. While these findings indicate a role of global histone deacetylation to promote correct gene regulation for entry into quiescence, they are also consistent with the role of bulk histone deacetylation to promote viability of the cells by providing acetate to sustain metabolism during the metabolic shift. Importantly, these two functions are not mutually exclusive. One might hypothesise that during evolution a metabolism-linked role of chromatin modification may have preceded or developed in parallel to the established signalling role. If chromatin has a role as metabolite reservoir, then this function may also be found in prokaryotes where chromatin is organised by abundant proteins, too. Indeed, chromatin proteins that are functionally (eubacteria) and evolutionary (archaea) related to histones are found to be acetylated [11.Carabetta V.J. Addressing the possibility of a histone-like code in bacteria.J. Proteome Res. 2021; 20: 27-37Crossref PubMed Scopus (5) Google Scholar,12.Alpha-Bazin B. et al.Lysine-specific acetylated proteome from the archaeon Thermococcus gammatolerans reveals the presence of acetylated histones.J. Proteome. 2021; 232104044Crossref PubMed Scopus (7) Google Scholar]. Noteworthy is the identification of lysine deacetylase Bkd1 that is able to shape the acetylome of the whooping cough agent Bordetella pertussis, including of chromatin associated histone-like proteins [13.Novak J. et al.Bordetella pertussis acetylome is shaped by lysine deacetylase Bkd1.J. Proteome Res. 2020; 19: 3680-3696Crossref PubMed Scopus (4) Google Scholar]. While deletion of Bkd1 affected virulence in a mouse model to some degree, the authors conclude that the lysine deacetylase and N-ε-lysine acetylation primarily modulate the general metabolism of B. pertussis [13.Novak J. et al.Bordetella pertussis acetylome is shaped by lysine deacetylase Bkd1.J. Proteome Res. 2020; 19: 3680-3696Crossref PubMed Scopus (4) Google Scholar]. Thus, at least in some prokaryotes, abundant histone-like proteins are modified by acetylation with a link to metabolism, suggesting that a potential reservoir function of chromatin may also exist in prokaryotes. Testing a reservoir function of chromatin for metabolites will be challenging, just alone because of the difficulty to trace and follow metabolites; for example, through heavy isotope labelling. Furthermore, not only have steady-state levels of metabolites to be considered, but also fluxes. Disentangling indirect effects via gene regulation from direct effects on metabolites will be a formidable challenge. Furthermore, most work in this context has been performed in yeast, and future studies should test a reservoir function of histone modifications in higher eukaryotes. Yet, the recent discovery that histones themselves have oxidoreductive functions highlight the importance to consider the nucleus a metabolic organelle [14.Attar N. et al.The histone H3-H4 tetramer is a copper reductase enzyme.Science. 2020; 369: 59-64Crossref PubMed Scopus (28) Google Scholar]. Considering a function of chromatin as a metabolite reservoir has the potential to throw new light onto old facts and will reveal additional roles of histone modification. We dedicate this piece to the memory of Jeffrey N. McKnight (1984–2020). We thank Marco Aurélio Ramirez Vinolo for support and discussion, Karoline Luger, Alexey Soshnev, and Jose C. Reyes for advice on the figures, Vladimir Teif for advice on nucleosome spacing in human cells and Joaquín de Navascués, Vladimir Teif, Charalampos Rallis, and N. Radu Zabet for comments that improved the manuscript. P.D.V.-W.'s work is supported by the University of Essex , a grant from N3CRs ( NC/W001047/1 ), and a FAPESP São Paulo Excellence Chairs special scheme ( 2019/16113-5 ); V.D.N. and D.R.d.P. by direct fellowships from FAPESP ( 2021/00393-9 , 2021/00398-0 ); and N.V.P.A. by a postdoctoral fellowship from FAPESP ( 2021/05269-4 ). No interests are declared.

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