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

Araújo, Nathália VP

Nirello, Vinícius D

Rodrigues de Paula, Dieggo

Varga-Weisz, Patrick D

University of Essex Research Repository

Trends inTIBS 1894 No. of Pages 4Biochemical SciencesForumDoes chromatin functionas ametabolite reservoir?Vinícius D. Nirello,1,4Dieggo Rodrigues de Paula,1,4Nathália V.P. Araújo,1,4 andPatrick D. Varga-Weisz 2,3,@,*Alternative histone acylationsintegrate gene expression withcellular metabolic states. Recentmeasurements of cellular acyl-coenzyme A (acyl-CoA) poolshighlight the potential that histonepost-translational modifications(PTMs) contribute directly to theregulation of metabolite pools. Ametabolite-centric view throwsnew light onto roles and evolutionof histone PTMs.The many roles of histone PTMsNuclear genomes are organised bynucleosomes composed of the histonecore around which the DNA winds inalmost two turns (Figure 1). Chromatinorganisation and function, such asgene regulation, is controlled by a mul-titude of histone PTMs that mostlyoccur on histone tails protruding fromthe nucleosomes (N-terminal for all his-tones and C-terminal for H1, H2A, andH2B) [1]. Histone PTMs control chro-matin structure by changing the chargeof histones affecting interaction withDNA (e.g., acetylation) and by creatingbinding sites for chromatin remodellingfactors [1]. Research of the pastdecade has underscored the closelink between histone PTMs and cellularmetabolic states [1–3]. As histonesare some of the most abundant cellularproteins and are highly modified,they have the potential to serve asa reservoir for metabolites suchas short chain carboxylic acids likeacetate through histone modifications[2] (Figure 1).Here, we discuss observations consistentwith the idea that chromatin serves asmetabolite reservoir, namely: (i) new in-sights into alternative histone acylationsand cellular acyl-CoA levels; (ii) the impor-tant role of histone deacetylation in cellularstates related to nutrient deprivation; and(iii) chromatin acetylation in prokaryotes.Acyl-CoA pools and histoneacylations are interlinkedAcyl-CoAs, composed of an acyl group(such a acetyl) linked by a thioester bondto cofactor coenzyme A, are critical foracyl transfer in lipid and amino acid syn-thesis and degradation, glycolysis, andthe tricarboxylic acid cycle [2–5]. As acyldonors, acyl-CoA molecules have the po-tential to exert signalling functions throughPTMs of proteins, especially histones,leading to acetylation, propionylation, andcrotonylation, among many others [1,3](Figure 1). The metabolism of acyl-CoAsis compartmentalised and enzymes thatproduce various acyl-CoA metabolitesare also present in the nucleus, highlight-ing the role of acyl-CoA in connectingcell metabolism to chromatin regulation(reviewed in [3], see [6] as an example).Histone acylations are closely linkedto the metabolic state of cells as theMichaelis constant KM of acyl transferasesfor acyl-CoAs are in the range of the acyl-CoA cellular concentrations. Therefore,there is a correlation between concentra-tions of different acyl-CoAs and the globalabundance of their respective histoneacylation with ensuing changes in geneexpression [1,3]. For example, the analysisof the yeast metabolic cycle (YMC) illus-trates how alternative histone acylations,acetylation, or crotonylation at lysine 9 ofhistone H3, link cellular metabolism togene regulation [7]. In the YMC, cyclicalalterations between high oxygen and lowoxygen consumption (LOC) are mirroredby cyclical global changes in histoneTrencrotonylation versus acetylation, with his-tone crotonylation promoted by fatty acidmetabolism (which generates crotonyl-CoA) at the LOC stage [7]. Another exam-ple illustrating the axis between specifichistone acylation and metabolism was un-covered using metabolite quantitation byliquid chromatography–mass spectrome-try [4]. Here, the authors demonstratedthat nuclear propionyl-CoA derives fromisoleucine catabolism and promotes his-tone propionylation, a mark linked to ac-tive gene expression at specific histonelysine residues.Histone acetylation and other histone acyl-ations are dynamic with half-lives of theorder of minutes and deac(et)ylation gen-erates short chain carboxylic acids, suchas acetate. The acetate can then be con-verted back to acetyl-CoA (Figure 2), andthis holds true also for many other acylgroups [2,3]. Thus, chromatin can be rap-idly loaded and unloadedwith acyl groups.Progress in accurately measuring subcel-lular acyl-CoA pools allows one to gaugehow these compare to the number ofmodifiable lysine residues on histones[4,5]. This indicates that the number ofacetate molecules that could be releasedfrom chromatin potentially exceeds thenumber of acetyl-CoA molecules in thecell by orders of magnitude at a giventime (Figure 1). Thus, histone acetylationhas the potential to act as an acetate res-ervoir, where the acetate can be releasedby deacetylases, for example, on starva-tion, to regenerate acetyl-CoA for energyproduction and anabolism [2] (Figure 2).Furthermore, recent papers provide evi-dence that acetate from histones releasedby histone deacetylases can be recycledfor histone modifications of other loci andother histone lysine residues on metabolicshifts, which in turn, is connected tochanges in gene expression [6,8]. Therecycling of acyl moieties potentially holdstrue for alternative histone acylations,such as propionylation or crotonylation.ds in Biochemical Sciences, Month 2022, Vol. xx, No. xx 1Trends in Biochemical SciencesFigure 1. Chromatin has the potential to act as a reservoir for acyl groups. We compared the numbers of lysine residues of histones that can be modified byacylation, for example, acetylation, with the number of measured total acetyl-CoA molecules in a cell. Lysine residues (K) that are well documented to be acetylated areindicated in the insert. The percentage of histone residues that are acetylated varies depending on residue, cell type, growth condition etc., but can be in the double-digit numbers [15]. Histone H1 has multiple lysine residues at both the C and N termini that are acetylated, but precise positions are less documented compared withthose in the core histones. Histone acylations described here as examples are illustrated on top. References used [4,5].Trends in Biochemical SciencesTherefore, one would expect that globalhistone acetylation drops on starvationand that histone deacetylases are impor-tant for viability during starvation. Studieson quiescence in yeast indicate thatthese predictions hold true.Role of histone deacetylationduring entry into quiescenceQuiescence is a reversible metabolic statein which cells temporarily abandon the cellcycle, exhibit a decrease in cell size, andshut down transcription and translation ofproteins, all leading to greater stress resis-tance. Several models show that changesin histone PTMs occur with quiescenceand are linked to a more compacted chro-matin state [9]. The McKnight et al. analy-sis of chromatin changes in buddingyeast Saccharomyces cerevisiae duringthe transition to quiescence highlights theimportance of histone deacetylation in2 Trends in Biochemical Sciences, Month 2022, Vol. xx, No.this process [10]. There are two distinctphases in budding yeast transition fromgrowth phase to quiescence after con-sumption of the medium’s glucose. Thefirst phase called diauxic shift consists ofthe stress response and shutdown of thetranscriptional machinery in response tocarbon source limitation, and the secondphase, quiescence itself, consists of lossof global histone acetylation and increasein occupation of promoter regions by nu-cleosomes. The quiescence process de-pends on the highly conserved Rpd3histone deacetylase: in the diauxic shift,Rpd3 targets genes related to ribosomebiosynthesis and function; during quies-cence, it represses about half of theknown genes of S. cerevisiae [10]. As aconsequence of Rpd3 function, an overalldramatic reduction in histone acetylationoccurs after entry into the quiescencestate and mRNA levels decrease 30-foldxxrelative to logarithmic growth [10]. Re-markably, deletion of RPD3 leads to a sig-nificant loss of viability of the cells enteringquiescence [10]. While these findings indi-cate a role of global histone deacetylationto promote correct gene regulation forentry into quiescence, they are alsoconsistent with the role of bulk histonedeacetylation to promote viability of thecells by providing acetate to sustain me-tabolism during the metabolic shift. Impor-tantly, these two functions are not mutuallyexclusive.Histone-like protein acetylationand cellular metabolism inprokaryotesOne might hypothesise that during evolu-tion a metabolism-linked role of chromatinmodification may have preceded or devel-oped in parallel to the established signal-ling role. If chromatin has a role asTrends in Biochemical SciencesFigure 2. Entry into quiescence is accompanied by histone deacetylase (HDAC)-mediated release of acetate from chromatin in budding yeast. Innutrient-rich conditions (left panel), glucose feeds into the TCA (Krebs) cycle in the mitochondria where it is converted into citrate which is exported into the cytosol.There, the citrate provides the acetyl groups for the enzyme ATP citrate lyase (ACLY) to generate acetyl-CoA, which, in turn, is used to mediate histone acetylation byhistone acetyltransferases (HATs). On entry into quiescence, HDACs, such as Rpd3, release acetate from histones, which can be used for energy production oranabolic reactions, such as amino acid or fatty acid synthesis, after being joined with CoA to generate acetyl-CoA by an acetyl-CoA synthetase (ACS) enzyme.Trends in Biochemical Sciencesmetabolite reservoir, then this functionmay also be found in prokaryotes wherechromatin is organised by abundant pro-teins, too. Indeed, chromatin proteins thatare functionally (eubacteria) and evolution-ary (archaea) related to histones are foundto be acetylated [11,12]. Noteworthy isthe identification of lysine deacetylaseBkd1 that is able to shape the acetylomeof the whooping cough agent Bordetellapertussis, including of chromatin associ-ated histone-like proteins [13]. While dele-tion of Bkd1 affected virulence in a mousemodel to some degree, the authorsconclude that the lysine deacetylase andN-ε-lysine acetylation primarily modulatethe general metabolism of B. pertussis[13]. Thus, at least in some prokaryotes,abundant histone-like proteins are modi-fied by acetylation with a link to metabo-lism, suggesting that a potential reservoirfunction of chromatin may also exist inprokaryotes.Concluding remarksTesting a reservoir function of chromatinfor metabolites will be challenging, justalone because of the difficulty to traceand follow metabolites; for example,through heavy isotope labelling. Further-more, not only have steady-state levels ofmetabolites to be considered, but alsofluxes. Disentangling indirect effects viagene regulation from direct effects on me-tabolites will be a formidable challenge.Furthermore, most work in this contexthas been performed in yeast, and futurestudies should test a reservoir function ofhistone modifications in higher eukaryotes.Yet, the recent discovery that histonesthemselves have oxidoreductive functionshighlight the importance to consider the nu-cleus a metabolic organelle [14]. Consider-ing a function of chromatin as a metabolitereservoir has the potential to throw newlight onto old facts and will reveal additionalroles of histone modification.TrenAcknowledgmentsWe dedicate this piece to the memory of Jeffrey N.McKnight (1984–2020).We thankMarcoAurélio RamirezVinolo for support and discussion, Karoline Luger, AlexeySoshnev, and Jose C. Reyes for advice on the figures,Vladimir Teif for advice on nucleosome spacing in humancells and Joaquín de Navascués, Vladimir Teif,Charalampos Rallis, and N. Radu Zabet for commentsthat improved the manuscript. P.D.V.-W.'s work is sup-ported by the University of Essex, a grant from N3CRs(NC/W001047/1), and a FAPESP São Paulo ExcellenceChairs 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 postdoc-toral fellowship from FAPESP (2021/05269-4).Declaration of interestsNo interests are declared.1International Laboratory for Microbiome Host Epigenetics,Department of Genetics, Evolution, Microbiology, andImmunology, Institute of Biology, University of Campinas,Campinas, SP, Brazil2São Paulo Chair of Excellence, International Laboratory forMicrobiome Host Epigenetics, Department of Genetics,Evolution, Microbiology, and Immunology, Institute of Biology,University of Campinas, Campinas, SP, Brazilds in Biochemical Sciences, Month 2022, Vol. xx, No. xx 3Trends in Biochemical Sciences3School of Life Sciences, University of Essex, Colchester, UK4Joint first authors.*Correspondence:Patrick.varga-weisz@essex.ac.uk (P.D. Varga-Weisz).@Twitter: @PatVargaWeisz (P.D. Varga-Weisz).https://doi.org/10.1016/j.tibs.2022.03.016© 2022 Elsevier Ltd. All rights reserved.References1. Nitsch, S. et al. (2021) Histone acylations and chromatindynamics: concepts, challenges, and links to metabolism.EMBO Rep. 22, e527742. Ye, C. and Tu, B.P. (2018) Sink into the epigenome: his-tones as repositories that influence cellular metabolism.Trends Endocrinol. Metab. 29, 626–6374 Trends in Biochemical Sciences, Month 2022, Vol. xx, No.3. Trefely, S. et al. (2020) Compartmentalised acyl-CoA me-tabolism and roles in chromatin regulation. Mol. Metab.38, 1009414. Trefely, S. et al. (2021) Quantitative subcellular acyl-CoAanalysis reveals distinct nuclear metabolism andisoleucine-dependent histone propionylation. Mol. Cell82, 447–462.e65. Jones, A.E. et al. (2021) A single LC-MS/MS analysis toquantify CoA biosynthetic intermediates and short-chainacyl CoAs. Metabolites 11, 4686. Mendoza, M. et al. (2022) Enzymatic transfer of acetate onhistones from lysine reservoir sites to lysine activatingsites. Sci. Adv. 8, eabj56887. Gowans, G.J. et al. (2019) Recognition of histonecrotonylation by Taf14 links metabolic state to gene ex-pression. Mol. Cell 76, 909–921.e38. Hsieh, W.-C. et al. (2022) Glucose starvation induces aswitch in the histone acetylome for activation of gluconeo-genic and fat metabolism genes. Mol. Cell 82, 60–74.e5xx9. Bonitto, K. et al. (2021) Is there a histone code for cellularquiescence? Front. Cell Dev. Biol. 9, 73978010. McKnight, J.N. et al. (2015) Global promoter targeting of aconserved lysine deacetylase for transcriptional shutoffduring quiescence entry. Mol. Cell 59, 732–74311. Carabetta, V.J. (2021) Addressing the possibility of ahistone-like code in bacteria. J. Proteome Res. 20, 27–3712. Alpha-Bazin, B. et al. (2021) Lysine-specific acetylated pro-teome from the archaeon Thermococcus gammatoleransreveals the presence of acetylated histones. J. 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Does chromatin function as a metabolite reservoir?

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Does chromatin function as a metabolite reservoir?

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