Linking cellular metabolism to chromatin modifications in plants

ABSTRACT

Beyond their traditional roles as biological building blocks and energy sources, metabolites also influence gene expression, exerting direct effects on the epigenetic landscape. For example, core metabolites such as acetyl coenzyme A (acetyl‐CoA) and S‐adenosylmethionine (SAM) serve as substrates or cofactors for chromatin‐modifying enzymes, thereby modulating transcription through the chemical modification of histones and DNA. In addition, metabolites regulate the transcription of the genes encoding these chromatin modifiers, as well as the post‐translational modifications and enzymatic activities of these proteins. Therefore, we propose that the metabolic state of a cell or organism is a dynamic and active driver of epigenomic reprogramming, adjusting gene expression in response to fluctuations in the environment.

Beyond their canonical roles in metabolism, cellular metabolites actively regulate the plant epigenome. This review highlights how metabolic intermediates directly modify DNA and histones, thereby linking environmental cues to gene regulation, and proposes that metabolism functions as a dynamic driver of epigenomic reprogramming that controls plant growth, development, and adaptation to environmental conditions.

INTRODUCTION

Living organisms modulate gene expression in response to developmental and environmental cues to acclimate to changing conditions. In plants, gene expression is actively regulated through the coordinated actions of transcription factors (TFs), transcriptional coregulators, and chromatin remodelers and modifiers. A key layer in this regulatory network is chromatin‐based epigenetic control, which modulates the accessibility of DNA to the transcriptional machinery, including TFs and RNA polymerases (RNA Pol), through the chemical modification of DNA and histones.

Epigenetic regulation primarily involves post‐translational modifications (PTMs) of histones, such as acetylation and methylation (Strahl and Allis, 2000). Because histones are rich in positively charged residues and form tight complexes with negatively charged DNA, PTMs that alter electrostatic interactions can directly influence chromatin structure and accessibility. For instance, lysine acetylation neutralizes the positive charge of histones, weakening histone–DNA interactions and promoting transcriptional activation (Shogren‐Knaak et al., 2006). Furthermore, these modifications are recognized in a residue‐ and structure‐specific manner by specific reader proteins (Taverna et al., 2007), which in turn interact with transcriptional regulators such as TFs, transcriptional coregulators, and chromatin remodelers, reinforcing the precise control of gene expression (Jing et al., 2013; López‐González et al., 2014; Su and Denu, 2016; Su et al., 2025).

With advancements in mass spectrometry, the list of PTMs detected on histones has substantially expanded (Jiang et al., 2021; Lu‐Culligan et al., 2023; Yu et al., 2023; Chen et al., 2024). In addition to canonical histone modifications such as arginine or lysine methylation and lysine acetylation, additional PTMs of histones have recently been identified, including lysine lactylation, glutamine serotonylation, glutamine dopaminylation, lysine isonicotinylation, lysine acetyl‐methylation, and tyrosine sulfation (Farrelly et al., 2019; Jiang et al., 2021; Lepack et al., 2020; Lu‐Culligan et al., 2023; Yu et al., 2023; Zhang et al., 2019). Although their precise biological functions remain to be elucidated, many of these PTMs are tightly linked to cellular metabolism, as cellular metabolic intermediates are used as substrates for the enzymatic reactions of histone modifications. This direct link raises the possibility that metabolism and chromatin modifications are interconnected in ways that were not fully appreciated previously (Katada et al., 2012; Lu and Thompson, 2012; Gut and Verdin, 2013).

Plants produce abundant, diverse primary and secondary metabolites, which have traditionally been viewed mainly as precursors in studies of end‐product biosynthesis and energy flow (Lunn, 2007; DeBerardinis and Thompson, 2012). However, these intermediates also function as signaling molecules (Wellen and Thompson, 2012; Baker and Rutter, 2023). For instance, glucose activates the target of rapamycin (TOR) pathway, leading to extensive transcriptional reprogramming (Xiong et al., 2013; Chen et al., 2022). Additionally, amino acids activate calcium (Ca²⁺) signaling via glutamate receptor‐like channels to regulate diverse aspects of cellular physiology in plants (Häusler et al., 2014; Yu et al., 2022). Secondary metabolites such as flavonoids, glucosinolates, and terpenes also modulate signaling pathways, possibly through direct binding to target signaling proteins (Erb and Kliebenstein, 2020; Wu et al., 2023).

One particularly intriguing aspect of metabolite‐mediated regulation in plants is the interplay between cellular metabolism and chromatin‐based gene regulation (Hu et al., 2019; Leung and Gaudin, 2020; Lindermayr et al., 2020; Samo et al., 2021; Huang and He, 2024). Indeed, metabolic activity is now thought to both reflect the internal physiological status of cells and to function as an active regulatory layer. Metabolite‐mediated regulation can take various forms. Some metabolites serve as substrates for enzymes that deposit PTMs on DNA and histones. Additionally, metabolites influence the activities of various chromatin modifiers, from transcription to posttranslational modifications. Building on this conceptual framework, in this review, we focus on the diverse mechanisms by which metabolic states influence chromatin‐dependent gene regulation, with an emphasis on recent findings in plant systems.

ROLES OF METABOLITES IN DIRECT CHROMATIN MODIFICATION

In the context of epigenetic regulation, metabolites serve as essential reactants for the chemical modification of DNA and histones. The greater availability of a reactant typically drives a higher rate of product formation. Thus, changes in the metabolic state or the accumulation of specific metabolites may influence the epigenetic landscape, positioning metabolites as direct molecular signals for the regulation of gene expression. This section highlights key studies that have established a link between metabolite availability and chromatin modifications.

S‐adenosylmethionine and methylation of histones and DNA

S‐adenosylmethionine (SAM, also known as AdoMet) is a well‐characterized methyl group donor in numerous methylation reactions (Finkelstein, 1990), including DNA and histone methylation. SAM is biosynthesized from the amino acid methionine (Met) and ATP via methionine adenosyltransferase (MAT), also called SAM synthetase (SAMS) (Boerjan et al., 1994). When SAM donates a methyl group, a reaction catalyzed by methyltransferases, it is converted into S‐adenosyl‐L‐homocysteine (SAH) (Watanabe et al., 2021; Lu et al., 2023), which is hydrolyzed into homocysteine and adenosine by SAH hydrolase (SAHH). Homocysteine is recycled back into Met by methionine synthase (MS). Collectively, these reactions form the activated methyl cycle, which maintains cellular methylation capacity (Rahikainen et al., 2018) (Figure 1A).

Figure 1.

Regulation of SAM biosynthesis and SAM‐dependent methylation of DNA and histones

(A) Linking SAM metabolism to epigenetic modification. S‐adenosylmethionine (SAM) is synthesized and regenerated through the activated methyl cycle. The size of the SAM pool is dynamically regulated by the availability of key metabolites, including methionine supplied by the folate cycle and S‐adenosylhomocysteine (SAH), the byproduct of SAM‐dependent methylation reactions. Enzymatic activity within the activated methyl cycle is critical for SAM homeostasis. (B) Environmental and developmental control of SAM metabolism and epigenetic states. The SAM synthesis pathway integrates environmental cues (such as salinity stress and pathogen infection) and developmental cues (in pollen) to modulate SAM levels. The tightly regulated SAM pool serves as the primary methyl donor for the epigenetic modification of DNA and histones, thereby influencing gene expression. MTHFD, methylenetetrahydrofolate dehydrogenase; FPGS, folylpolyglutamate synthetase; SAHH, SAH hydrolase; MS, methionine synthase; ADK, adenosine kinase; HMT, histone methyltransferase; DNMT, DNA methyltransferase; THF, tetrahydrofolate; 5‐CH₃‐THF, 5‐methyl‐THF; 5,10‐CH₂‐THF, 5,10‐methylene‐THF; 5,10 = CH₂‐THF, 5,10‐methenyl‐THF; THF‐Glu_n, THF polyglutamate; and TEs, transposable elements.

SAM is a substrate for various epigenetic modifications. The activity of the SAM biosynthetic enzyme MAT3 is positively correlated with the level of histone H3 lysine 9 dimethylation (H3K9me2) (Meteignier et al., 2022). In Arabidopsis (Arabidopsis thaliana), MAT3 is expressed in pollen (Loraine et al., 2013) and contributes to the silencing of transposable elements (TEs) through enhanced H3K9me2 deposition, especially in male gametophytes, thereby safeguarding genome integrity (Ibarra et al., 2012). In pollen, SAM is also important for maintaining the methylation of genomic DNA and transfer RNA (tRNA), ensuring normal pollen growth and development (Calarco et al., 2012; Chen et al., 2016; Fang et al., 2021) (Figure 1B).

In addition, the accumulation of SAM promotes stress tolerance through epigenetic modifications. Met, the precursor of SAM, accumulates to higher levels under stress conditions, which may confer greater stress tolerance to plants via alterations in DNA methylation levels (El‐Bauome et al., 2022; Shi et al., 2025). Consistent with this idea, overexpression of SlSAMS1 in tomato (Solanum lycopersicum) increased drought and salinity stress tolerance (Zhang et al., 2020), at least in part through DNA hypermethylation of stress‐responsive genes, including Gigantea (SlGI), which enhances tolerance to salinity stress (Chen et al., 2023) (Figure 1B).

By contrast, the mutation of MAT/SAMS genes leads to lower SAM levels, thereby impairing the methylation of DNA, histones, and tRNA (Shen et al., 2002; Chen et al., 2016). In Arabidopsis, mat4 mutants showed reduced levels of DNA methylation and H3K9 methylation, along with developmental defects that were rescued by SAM treatment (Meng et al., 2018). In rice (Oryza sativa), knockdown of SAMS also resulted in diminished H3K4me3 and DNA methylation levels. In particular, SAMS knockdown plants flowered later than the wild type due to lower global H3K4 trimethylation levels, which resulted in low expression of key flowering genes such as Early heading date 1 (Ehd1), Heading date 3a (Hd3a), and RICE FLOWERING LOCUS T (RFT1) (Li et al., 2011).

SAH competitively inhibits SAM‐dependent methylation by binding to methyltransferases (Bai et al., 2018). Therefore, the SAM/SAH ratio is a critical determinant of cellular methylation potential. SAHH is essential for SAH degradation, and its loss‐of‐function mutants accumulate SAH, resulting in lower SAM/SAH ratios and diminished DNA and histone methylation patterns in various plant species (Tanaka et al., 1997; Fojtová et al., 1998; Furner et al., 1998; Rocha et al., 2005; Mull et al., 2006; Baubec et al., 2010; Fulneček et al., 2011; Ouyang et al., 2012; Lindermayr et al., 2020). Notably, controlling the levels of adenosine and homocysteine, which are products of SAH hydrolysis, is also crucial for SAM‐dependent epigenetic regulation. Adenosine is phosphorylated to adenosine monophosphate (AMP) by adenosine kinase (ADK). Arabidopsis mutants deficient in ADK accumulate SAH, leading to lower SAM‐dependent methylation activity and thus DNA methylation (Moffatt et al., 2002). MS recycles homocysteine back into Met; its loss of function led to a lower SAM/SAH ratio, causing DNA hypomethylation and growth defects that were rescued by Met feeding (Yan et al., 2019).

Folate metabolism interconverts tetrahydrofolate (THF) derivatives, which serve as carriers of one‐carbon (C1) units for the SAM cycle, particularly during Met biosynthesis (Lindermayr et al., 2020; Watanabe et al., 2021; Ramakrishnan et al., 2022) (Figure 1A). Folates accumulate to high levels in plant tissues characterized by high metabolic rates and rapid cell division, such as embryos (Jabrin et al., 2003). Folate accumulation leads to the accumulation of SAM, which allows epigenetic silencing of TEs, thus enhancing genome stability. The key enzymes in the folate cycle that generate methyl group donors such as polyglutamylated THF include methylenetetrahydrofolate dehydrogenase and folylpolyglutamate synthetase. Mutations of the genes encoding these enzymes lead to a global loss of DNA methylation and H3K9me2 deposition, accompanied by the derepression of TEs (Zhou et al., 2013; Groth et al., 2016). Consistent with this observation, chemical inhibitors such as sulfamethazine disrupt folate biosynthesis, lowering 5‐methyl‐THF levels and consequently diminishing the extent of DNA and histone methylation in Arabidopsis (Zhang et al., 2012).

Folate‐dependent DNA methylation is also linked to plant immunity. Overexpression of MS, which encodes the final enzyme in the folate metabolic pathway, increases genome‐wide DNA methylation and compromises resistance to Pseudomonas syringae DC3000 (Pst DC3000), whereas treatment with sulfadiazine, a folate biosynthesis inhibitor, enhances resistance to Pst DC3000, implying a trade‐off between plant growth and defense (González and Vera, 2019). In agreement with this, infection with Pst DC3000 suppresses folate biosynthesis by downregulating dihydropteroate synthase, suggesting that plants actively modulate methyl‐cycle metabolism and thus their epigenetic landscapes as part of their immune strategies (González and Vera, 2019) (Figure 1B).

Given that SAM serves as a universal methyl donor for both active (e.g., H3K4me) and repressive (e.g., H3K9me) histone marks, how methyl‐cycle metabolites selectively influence opposing chromatin states remains unclear. Different histone methyltransferase complexes may show distinct sensitivities to local SAM availability. Elucidation of these mechanisms will be crucial for predicting transcriptional outcomes of metabolic fluctuations. Collectively, multiple metabolic pathways that ultimately influence SAM accumulation directly affect the global methylation of DNA and histones, shaping gene expression patterns as a function of metabolite status.

Acetyl‐CoA and histone acetylation

Alongside histone methylation, histone acetylation was one of the earliest PTMs discovered on histones (Allfrey et al., 1964). This PTM of histones typically facilitates transcriptional activation through the formation of an open chromatin configuration (Struhl, 1998; Görisch et al., 2005). Histone acetyltransferases (HATs) catalyze the deposition of this PTM by transferring acetyl groups from acetyl‐CoA to specific lysine residues on histones. Thus, the cellular acetyl‐CoA status is a crucial input for the epigenetic regulation of gene expression through histone acetylation.

Acetyl‐CoA is a key metabolic intermediate involved in the biosynthesis of amino acids, lipids, and secondary metabolites essential for plant growth and development (Shen et al., 2015). In plants, ATP‐citrate lyase (ACL) is the primary enzyme responsible for generating cytosolic acetyl‐CoA from citrate (Wellen et al., 2009). ACL genes are highly expressed in metabolically active tissues, such as the epidermis of developing organs and developing seeds (Fatland et al., 2002). In support of this finding, mutations of ACL genes lead to developmental defects of the endosperm and root meristem in rice (Xu et al., 2023). Notably, ACL activity is associated with histone acetylation, as lower ACL activity is accompanied by diminished histone acetylation levels due to a smaller available acetyl‐CoA pool in Arabidopsis (Chen et al., 2017). In parallel, ACL subunit A2, which forms a complex with HAT1 in the nucleus, promotes histone H4K5 acetylation at loci involved in carbohydrate metabolism in rice (Xu et al., 2023), suggesting that metabolites contribute to chromatin‐dependent regulation of gene expression to coordinate plant metabolism and development.

Given that multiple biosynthetic pathways feed into and draw from the cellular acetyl‐CoA pool, histone acetylation can be modulated by directly manipulating the enzymes that produce acetyl‐CoA or by altering neighboring metabolic pathways. For instance, since acetyl‐CoA carboxylases (ACCases) consume acetyl‐CoA for fatty acid biosynthesis (Yanai et al., 1995), the mutation of ACCase results in the accumulation of acetyl‐CoA, in turn leading to higher histone H3 lysine 27 acetylation (H3K27ac) levels. By contrast, the fatty acid β‐oxidation pathway serves as an important source of acetyl‐CoA (Hu et al., 2019). Mutations of the genes encoding β‐oxidation‐related enzymes such as ACYL‐COA OXIDASE 4 (ACX4), MULTIFUNCTIONAL PROTEIN 2 (MFP2), and 3‐KETOACYL‐COA THIOLASE 2 (KAT2) lead to a smaller acetyl‐CoA pool and globally lower histone acetylation levels in Arabidopsis (Wang et al., 2019). Meanwhile, the acx4 mutants also show locus‐specific DNA hypermethylation, suggesting a potential antagonistic relationship between histone acetylation and DNA methylation (Wang et al., 2019).

Acetyl‐CoA production is also enhanced by glycolysis, which drives the accumulation of pyruvate and acetate, which are key precursors of acetyl‐CoA biosynthesis (Ke et al., 2000). In mammals, the nucleus‐localized pyruvate dehydrogenase complex (PDC), which converts pyruvate into acetyl‐CoA in the nucleus, promotes histone acetylation (Sutendra et al., 2014). In plants, the PDC physically interacts with the C‐terminus of ETHYLENE INSENSITIVE 2 (EIN2), a regulator of ethylene signaling in Arabidopsis. Upon ethylene treatment, the PDC is translocated from the mitochondria to the nucleus and facilitates the direct EIN2‐dependent histone acetylation of its cognate target genes (Shao et al., 2024). Furthermore, enhanced glycolytic activity and acetyl‐CoA metabolism are associated with elevated histone acetylation and altered gene expression patterns, including those of growth‐promoting genes in rice (Ma et al., 2023).

Acetate and acetyl‐CoA accumulate under water‐deficit conditions. Greater flux through the tricarboxylic acid (TCA) cycle contributes to the accumulation of acetyl‐CoA under drought stress conditions. Consistent with this finding, overexpressing acetyl‐CoA synthetase (ACS), which encodes the enzyme that converts acetate to acetyl‐CoA, boosted drought tolerance, coinciding with increased acetyl‐CoA production and elevated global histone acetylation (Xia et al., 2024). Similarly, acetate treatment increased intracellular acetyl‐CoA levels (via the action of ACS) and thus histone acetylation levels at jasmonate‐related genes, which in turn activated drought‐related genes, enhancing drought tolerance in several plant species (Kim et al., 2017; Xia et al., 2024). This finding raises the possibility that stress‐induced changes in acetyl‐CoA levels regulate stress responses by reprogramming the histone acetylation landscape. Overall, environmental and metabolic cues that alter acetyl‐CoA availability globally affect the epigenetic landscape by reshaping histone acetylation profiles, thereby enabling plants to balance growth and stress resilience (Figure 2).

Figure 2.

Interplay between the cellular acetyl‐CoA pool and histone acetylation

Plants achieve acetyl‐CoA homeostasis by maintaining the dynamic balance between its production from various catabolic pathways and its utilization in metabolic and regulatory programs. Although cytosolic acetyl‐CoA is primarily generated from citrate via ATP‐citrate lyase (ACL), additional sources, including fatty acid β‐oxidation and glycolysis, also contribute to the cellular acetyl‐CoA pool. The availability of acetyl‐CoA influences histone acetylation levels, which in turn modulate the expression of downstream genes, linking cellular metabolic status to chromatin‐based regulation of gene expression. ACCase, acetyl‐CoA carboxylase; PDC, pyruvate dehydrogenase complex; ACS, acetyl‐CoA synthetase; ACX4, acyl‐CoA oxidase 4; MFP2, multifunctional protein 2; KAT2, 3‐ketoacyl‐CoA thiolase‐2; and HAT, histone acetyltransferase.

Methylglyoxal and histone methylglyoxalation

In plants, methylglyoxal (MG), a reactive by‐product of glycolysis, accumulates in response to various biotic and abiotic stress conditions (Chen et al., 2004; Yadav et al., 2005; Gowans et al., 2019). Although MG has long been considered a toxic metabolic by‐product due to its ability to disrupt cellular reactions and inhibit cell proliferation (Yadav et al., 2005; Hoque et al., 2012), accumulating evidence suggests that MG is also an active signaling molecule (Kaur et al., 2014; Li, 2016). Notably, MG forms covalent adducts with lysine and arginine residues on histones, resulting in histone methylglyoxalation (Galligan et al., 2018).

Indeed, recent studies have shown that MG can modulate gene expression through the non‐enzymatic modification of histones. Like histone acetylation, histone methylglyoxalation promotes chromatin relaxation and is associated with transcriptional activation (Fu et al., 2021). For instance, salinity stress increases MG levels in plants (Yadav et al., 2005), suggesting a potential regulatory role in stress responses. MG is primarily detoxified by the glyoxalase system, comprising GLYOXALASE I (GLYI) and GLYII, which convert MG into D‐lactate using glutathione as a cofactor (Kaur et al., 2014). In Arabidopsis, the mutation of GLYI2 leads to elevated MG levels and results in greater H3 methylglyoxalation, especially at salinity stress‐responsive loci (Fu et al., 2021). These findings support the idea that MG promotes a type of histone modification that serves as a dynamic epigenetic mechanism for plant acclimation to environmental stress.

Other metabolites related to recently discovered types of histone modifications

There has been growing interest in histone acylation as a metabolic sensor due to the important roles of acyl‐CoA in diverse metabolic pathways (Simithy et al., 2017; Trefely et al., 2020). Although histone acetylation has been extensively studied, other forms of histone acylation, such as butyrylation, crotonylation, and lactylation, remain relatively underexplored in plants. Nevertheless, increasing evidence links these modifications to plant responses to metabolic stress.

Given that submergence and nutrient deprivation, which limit energy production, are closely tied to lipid metabolism, it is plausible that these conditions influence the levels of acyl‐CoA, thereby affecting histone acylation patterns and the regulation of gene expression (Xie et al., 2021; Westerveld and Petracca, 2024). Under energy‐limiting conditions, enhanced β‐oxidation of fatty acids leads to the accumulation of butyryl‐CoA and crotonyl‐CoA (Abdinejad et al., 1981; Westerveld and Petracca, 2024). Additionally, amino acid catabolism offers an alternative route for the production of crotonyl‐CoA (Westerveld and Petracca, 2024). These metabolic shifts promote the accumulation of specific acyl‐CoA species, generating a cellular environment in which they can act as alternative substrates for HATs. Indeed, starvation and submergence conditions dynamically enhanced histone butyrylation and crotonylation profiles in rice, especially at stress‐induced genes (Lu et al., 2018), supporting a role for these acyl marks in transcriptional reprogramming during environmental stress (Figure 3).

Figure 3.

Diverse metabolites act as substrates for histone PTMs

Metabolic intermediates such as methylglyoxal (MG), butyryl‐CoA, crotonyl‐CoA, lactyl‐CoA, and 2‐hydroxyisobutyryl‐CoA serve as substrates for previously missed histone PTMs in plants. Environmental stress factors dynamically reshape plant metabolism, leading to changes in histone modifications that modulate gene expression. This diagram illustrates how diverse metabolic states influence histone PTMs, highlighting the roles of metabolites in fine‐tuning plant epigenetic responses to environmental cues.

Lactate levels decrease under drought stress in maize (Zea mays); this metabolite may affect drought tolerance, possibly through changes in histone lysine lactylation patterns (Shi et al., 2023). In line with this, the application of spermidine, a polyamine compound that enhances drought tolerance in plants (Li et al., 2018a), altered both lactate levels and histone lysine lactylation patterns (Shi et al., 2023), suggesting that cellular metabolite pools are dynamically adjusted under water‐deficit conditions (Figure 3). Moreover, oxygen deprivation is known to cause a rapid increase in intracellular lactate (Beamer et al., 2021; Fu and Xu, 2023). Because increased lactate level directly promotes histone lactylation, this modification is likely to function as a regulatory mechanism not only during hypoxia but also under drought stress (Zhang et al., 2019). Thus, dynamic changes in histone lactylation, driven by stress‐induced fluctuations in cellular lactate levels, appear to represent an adaptive strategy for reprogramming gene expression in response to various environmental stresses.

Histone lysine β‐hydroxybutyrylation has been identified in various plant species. In rice, histone lysine β‐hydroxybutyrylation levels increase upon β‐hydroxybutyrate treatment, enhancing the expression of disease‐resistance genes, likely through H3K9 hydroxybutyrylation at their promoter regions (Xie et al., 2016; Xu et al., 2025). Notably, the expression of the gene encoding acetoacetyl‐CoA thiolase, a key enzyme for the production of acetoacetyl‐CoA (the precursor of β‐hydroxybutyryl‐CoA), is upregulated when plants are infected by pathogens (Tsuda et al., 2016; Xiong et al., 2023), suggesting that pathogen‐induced reprogramming of metabolite flux reinforces chromatin‐dependent immune gene regulation (Figure 3).

Histone lysine 2‐hydroxyisobutyrylation (Khib) is another histone acylation that is related to glycolytic flux. In human cells, 2‐hydroxyisobutyrate, which is produced at higher levels in individuals with obesity and diabetes (metabolic diseases associated with altered glycolytic rates), acts as the donor for this histone PTM (Calvani et al., 2010; Vangipurapu et al., 2020). In budding yeast (Saccharomyces cerevisiae), H4K8hib is also closely linked to glycolysis; mutations of key genes encoding enzymes in the glycolysis pathway, such as those involved in fructose‐1,6‐bisphosphate metabolism, inhibit the glucose‐induced deposition of H4K8hib (Huang et al., 2017), suggesting that active glycolysis may elevate 2‐hydroxyisobutyrate levels, thereby increasing histone Khib levels. This is also the case in plants under darkness‐induced starvation conditions, where Khib co‐localizes with H3K23ac on histones, reprogramming gene expression to help plants adjust to energy deprivation (Zheng et al., 2021) (Figure 3). In summary, metabolites can be used as substrates for histone modifications that directly affect gene expression, linking metabolic status to gene expression.

MULTIPLE LAYERS OF REGULATING EPIGENETIC MODIFIER ACTIVITIES BY METABOLITES

Beyond serving as substrates for chromatin‐modifying enzymes, metabolites also directly modulate the activities of epigenetic enzymes. The function of these enzymes is tightly regulated at multiple levels, including the transcriptional control of their encoding genes, control of their activity by PTMs, and conformational changes that determine their activity and stability (Li et al., 2018b). Therefore, metabolites play crucial roles in fine‐tuning the activities of chromatin modifiers, with the potential to globally reshape chromatin architecture and gene expression patterns. In this section, we explore the emerging evidence linking cellular metabolic status to the regulation of enzyme activity related to the establishment or maintenance of the epigenetic landscape. We focus on studies providing mechanistic evidence explaining how metabolites control the activity of epigenetic modifiers and thus the global epigenetic landscape (Figure 4A–D).

Figure 4.

Multiple layers of regulation of epigenetic modifiers by metabolites

Metabolites influence the epigenetic landscape through multiple regulatory layers, including transcriptional regulation, post‐translational modifications (PTMs), cofactor availability, and protein–protein interactions with epigenetic modifiers. (A) Transcriptional regulation of epigenetic modifiers. Metabolite signaling can reprogram the transcriptional state, thereby regulating the expression of genes encoding epigenetic modifiers, thus influencing the global epigenetic landscape. For example, nitric oxide (NO) induces DNA hypomethylation by downregulating DNA methyltransferases. N‐acetylglutamate (NAG) accumulation enhances HAT gene expression, increasing histone acetylation. (B) Post‐translational modifications (PTMs) of histone modifiers. Metabolites can serve as substrates for the PTM of epigenetic modifiers, thereby altering the activities of these enzymes. In rice, acetyl‐CoA availability promotes lysine acetylation and degradation of ADA2, thereby maintaining histone acetylation homeostasis. In addition, NO activates PRMT5 to enhance histone H4 methylation, while inhibiting HDAC and JMJ activity, collectively elevating histone acetylation and methylation levels. (C) Enzyme cofactor availability. The activity of epigenetic modifiers is dependent on the availability of key metabolic cofactors. The cellular levels of these cofactors serve as direct metabolic inputs that modulate the activities of chromatin‐modifying enzymes, thereby affecting the global epigenetic landscape. α‐ketoglutarate (α‐KG) levels regulate JMJ demethylase activity and histone methylation states. Similarly, NAD⁺ availability enhances sirtuin‐mediated histone deacetylation. (D) Interactions of epigenetic modifiers with transcription factors (TFs) at specific chromatin loci. Metabolites can influence the interactions between TFs and modifiers, guiding epigenetic modifiers to specific loci. For instance, low glucose promotes the association of HAT with phosphorylated SnRK1, enabling their recruitment to bZIP‐target genes. High glucose promotes HAC1–WRKY interactions to activate sugar‐responsive genes in a histone acetylation‐dependent manner. NO, nitric oxide; NAG, N‐acetylglutamic acid; α‐KG, α‐ketoglutarate; NAD, nicotinamide adenine dinucleotide; SnRK1, Snf1‐related kinase 1; CMT3, CHROMOMETHYLASE 3; DDM1, DECREASE IN DNA METHYLATION 1; HAC, HISTONE ACETYLTRANSFERASE OF THE CBP FAMILY; ADA2, ADAPTOR 2; ADA3, ADAPTOR 3; SGF, SAGA‐ASSOCIATED FACTOR; GCN5, GENERAL CONTROL NON‐REPRESSED PROTEIN 5; PRMT5, PROTEIN ARGININE METHYLTRANSFERASE 5; HDAC, histone deacetylase; JMJ, Jumonji C domain‐containing histone demethylase; SRT, Sirtuin; HAT, histone acetyltransferase; and bZIP63, basic leucine zipper 63.

Transcriptional regulation by metabolites

Metabolites can modulate the expression of genes encoding epigenetic modifiers. For instance, the gaseous signaling molecule nitric oxide (NO) modulates the epigenetic landscape. In rice, NO treatment induced global DNA hypomethylation, predominantly at CHG sites (Ou et al., 2015), by transcriptionally downregulating CHROMOMETHYLASE 3 (CMT3) and DECREASE IN DNA METHYLATION 1 (DDM1) (Numa et al., 2015; Ou et al., 2015; Fang et al., 2022), suggesting that NO modulates the accumulation of transcripts for genes encoding epigenetic modifiers to reprogram the global chromatin landscape.

N‐acetylglutamic acid (NAG) is produced from glutamate in the arginine biosynthetic pathway. This metabolic intermediate likely accumulates in response to abiotic stress and confers stress tolerance. Heterologous overexpression of tomato N‐acetyl‐L‐glutamate synthase 1 (SlNAGS1) in Arabidopsis enhanced tolerance to abiotic stress (Kalamaki et al., 2009). Notably, NAG accumulation induces the expression of the HAT genes, HISTONE ACETYLTRANSFERASE OF THE CBP FAMILY 1 (HAC1) and HAC12, and allows global histone acetylation at genes related to oxidative stress, thereby alleviating oxidative damage (Hirakawa et al., 2023). Therefore, metabolites participate in the transcriptional control of genes encoding epigenetic modifiers and the global chromatin landscape, shaping the expression of a wide range of genes involved in plant acclimation to specific environments (Figure 4A).

Regulation of PTMs of chromatin modifiers by metabolites

Since metabolites serve as essential substrates for the PTM of proteins, the activity of chromatin modifiers can be modulated by metabolite‐induced protein PTMs. For example, the availability of acetyl‐CoA, a central metabolite with highly variable cellular abundance (Oliver et al., 2009), is essential for histone acetylation, but this chromatin modification is further balanced by regulatory mechanisms within a HAT complex module consisting of ADAPTOR 2 (ADA2), ADA3, SAGA‐associated factor (SGF), and GENERAL CONTROL NON‐REPRESSED PROTEIN 5 (GCN5) (Vlachonasios et al., 2021). In the presence of high acetyl‐CoA levels, ADA2 undergoes lysine acetylation, leading to its degradation, thereby balancing histone acetylation levels in rice (Yu et al., 2024).

NO modulates the activities of various chromatin‐modifying enzymes through PTMs, such as tyrosine nitration, cysteine S‐nitrosylation, and metal nitrosylation (Lindermayr et al., 2020). In Arabidopsis, NO directly regulates the activity of PROTEIN ARGININE METHYLTRANSFERASE 5 (PRMT5), which catalyzes the methylation of histone proteins via S‐nitrosylation of its Cys‐125 residue. This residue‐specific S‐nitrosylation enhances the enzymatic activity of PRMT5, thereby increasing histone H4 methylation. This mechanism is activated particularly under salinity stress conditions, when NO levels increase and promote the S‐nitrosylation modification of PRMT5. Genome‐wide histone H4 methylation may contribute to stress tolerance in Arabidopsis (Hu et al., 2017). This NO‐mediated regulatory pathway is not limited to salinity stress responses but may also enhance plant resistance to pathogen infection through the NO burst and PRMT5‐catalyzed H4 methylation as shown in potato (Solanum tuberosum) (Drozda et al., 2022), emphasizing the NO‐dependent enhancement of PRMT5 activity in plant responses to various biotic and abiotic stresses.

NO also suppresses the activities of Jumonji C domain‐containing histone demethylases (JMJs) via nitrosylation of the iron cations in their catalytic pockets in mammalian cells (Hickok et al., 2013). Given that the structure of JMJs is conserved between mammals and plants, it is plausible that NO exerts a similar inhibitory effect in plants and may globally affect the epigenetic landscape (Ageeva‐Kieferle et al., 2019; Ma et al., 2022). Similarly, NO‐induced S‐nitrosylation of histone deacetylase (HDAC) inhibits its activity, leading to higher histone acetylation levels in Arabidopsis (Mengel et al., 2017). Gene ontology (GO) enrichment analysis of genes affected by NO‐mediated acetylation revealed the enrichment of stress‐related genes. Given that stress treatments induce the accumulation of NO, the NO‐induced histone acetylation of stress‐responsive loci will promote their transcriptional activation and thus confer stress tolerance (Mengel et al., 2017; Ageeva‐Kieferle et al., 2021). Taken together, these observations indicate that metabolites serve as substrates or regulators that affect the PTMs of chromatin modifiers and thereby modulate the epigenetic landscape (Figure 4B).

Regulation of epigenetic modifier activity by metabolite cofactors

The enzymatic activity of chromatin modifiers is closely tied to the availability of specific metabolites that act as their cofactors (Figure 4C). For example, JMJs require ferrous iron [Fe(II)] and α‐ketoglutarate (α‐KG) as cofactors to demethylate the lysine residues of histones (Tsukada et al., 2006). Indeed, the availability of α‐KG affects histone demethylation activity (Carey et al., 2015). α‐KG is converted into succinyl‐CoA by α‐ketoglutarate dehydrogenase (KGDH) in the TCA cycle (Hansen and Gibson, 2022). In Arabidopsis, cytoplasmic KGDH enters the nucleus upon light exposure, where it consumes nuclear α‐KG, limiting JMJ activity and increasing histone methylation at JMJ‐target genes (Huang et al., 2023). Likewise, succinate, a competitor of α‐KG, inhibits JMJ activity (Xiao et al., 2012; Huang et al., 2023). By contrast, cytosolic isocitrate dehydrogenases (cICDHs), which synthesize α‐KG, enhance the activity of JMJ14. Arabidopsis loss‐of‐function mutants of cICDH showed lower α‐KG levels and higher trimethylation of H3K4 than the wild type (Cui et al., 2021). These findings highlight how plants fine‐tune histone demethylation by modulating the availability of α‐KG.

Nicotinamide adenine dinucleotide (NAD) regulates the redox status of plant cells. The cellular NAD⁺ pool enhances the activities of Sirtuin (SRT) enzymes, a conserved family of NAD⁺‐dependent HDACs (König et al., 2014; Mitra and Dey, 2022). Notably, this regulatory axis is important for plant responses to abiotic stress. Changes in cellular NAD⁺ levels may confer salinity stress tolerance in plants (Wei et al., 2020), possibly in an SRT‐dependent manner, by regulating H3K9ac levels at stress‐responsive genes (Zhong et al., 2013; Tang et al., 2022).

Regulation of interactions between chromatin modifiers and TFs by metabolites

Chromatin modifiers typically lack intrinsic specificity for particular genomic loci and tend to alter the epigenetic landscape on a global scale. Specific metabolites, however, often induce changes in gene expression from a limited number of loci essential for a corresponding physiological response, rather than causing broad epigenetic changes. This context‐dependent regulation is likely mediated through metabolite‐driven control of interactions between chromatin modifiers and TFs (Figure 4D).

A compelling example comes from the sugar signaling pathway in Arabidopsis (Chen et al., 2022). In response to glucose, the histone acetyltransferase HAC1 interacts with the TFs WRKY18 and WRKY53 to promote histone acetylation at sugar‐responsive genes (Chen et al., 2019). Further, glucose treatment also downregulates HAC1 expression (Heisel et al., 2013), suggesting a feedback mechanism that fine‐tunes transcriptional responses to metabolic inputs.

Another example involves Snf1‐related kinase 1 (SnRK1), a central energy sensor activated under low‐glucose conditions (Baena‐González et al., 2007). In energy‐limiting states, SnRK1 phosphorylates the TF basic leucine zipper 63 (bZIP63), which recruits HATs to regulate histone acetylation at its target genes in Arabidopsis (Pedrotti et al., 2018). Taken together, these findings highlight how global metabolic shifts influence the activities of specific TFs, which in turn recruit chromatin modifiers to particular genomic regions. This interplay ensures that metabolic signals are translated into gene expression programs in a precise, context‐dependent manner.

CONCLUDING REMARKS AND FUTURE PROSPECTS

Metabolic pathways underpin every facet of the plant life cycle, orchestrating a vast array of biological reactions that govern growth, reproduction, stress acclimation, and ultimately, crop yield. In response to diverse environmental challenges, such as biotic and abiotic stress, plants undergo extensive metabolic reprogramming, which supports their survival and profoundly influences their developmental plasticity (Neilson et al., 2013; Obata et al., 2015; Razzaq et al., 2019). To fully understand plant adaptation, it is imperative to look beyond the classic roles of metabolites and appreciate the emerging functions of metabolites as signaling molecules. It is increasingly evident that metabolic status reflects the internal acclimatory responses of plants to environmental stimuli. Metabolites actively participate in signaling networks that integrate metabolic cues with gene expression, thereby ensuring appropriate physiological responses. Notably, recent insights into the metabolite–epigenome interface reveal a new paradigm: the availability of metabolites as substrates for chromatin‐modifying enzymes fine‐tunes epigenetic states and transcriptional regulation. Metabolites also regulate the activities of chromatin modifiers by affecting the transcription of their encoding genes, their PTMs, their conformational changes, and/or protein–protein interactions, thereby reshaping the epigenetic landscape.

Despite these recent advances, our understanding of the interplay between plant metabolism and the epigenome remains incomplete. Many histone PTMs derived from cellular metabolites are still largely unexplored, and the regulatory roles of various metabolites in plants have yet to be fully elucidated. Advances in mass spectrometry provide new avenues for the identification of new types of histone modifications. For example, histone lactylation, a recently characterized PTM, is directly regulated by intracellular levels of lactate, which accumulates through active glycolysis in cancer cells and modulates gene expression related to tumor progression (Lv et al., 2023; Zhang et al., 2019). Likewise, histone crotonylation levels fluctuate during the cell cycle and are positively correlated with fatty acid β‐oxidation, which generates crotonyl‐CoA during cell division (Gowans et al., 2019). These modifications have primarily been studied in animals; their potential counterparts in plants and their links to plant metabolism are largely uninvestigated.

In addition, diverse mechanisms through which metabolites regulate the activities of chromatin modifiers are beginning to emerge. In mammals, fumarate has been shown to inhibit JMJ‐type histone demethylases, similar to the effect of succinate (Xiao et al., 2012). Short‐chain fatty acids such as β‐hydroxybutyrate and butyrate inhibit HDACs, thereby activating gene expression (Candido et al., 1978; Shimazu et al., 2013). Hydrogen peroxide and flavin adenine dinucleotide (FAD) influence the redox state and the activity of FAD‐dependent histone demethylases (Hino et al., 2012; Niu et al., 2015), suggesting that redox regulation may also play a role in chromatin remodeling. Numerous plant‐derived secondary metabolites, including flavonoids, terpenoids, alkaloids, quinones, polyphenols, and isothiocyanates, are bioactive compounds with anti‐cancer properties due to their regulation of mammalian epigenetic modifier activity (Thakur et al., 2014; El Omari et al., 2021). Given their effects on mammalian cells, it is possible that plant secondary metabolites alter epigenetic modifiers and the chromatin landscape in their plants of origin, further expanding the repertoire of metabolite‐regulated epigenetic mechanisms.

Unraveling this metabolic–epigenetic network represents a major frontier in plant biology. Systematic mapping of these interactions will provide deeper insight into how plants integrate metabolic status with chromatin dynamics to mount the appropriate responses to their environment. Furthermore, it is important to unveil how metabolites affect epigenetic changes globally and how they selectively influence context‐dependent chromatin modifications to activate specific biological programs in response to the accumulation of specific metabolites. Ultimately, this integrated perspective on metabolism and epigenetics offers a new direction for epigenetic innovation and sustainable crop improvement (Gupta and Salgotra, 2022; Kakoulidou et al., 2021; Varotto et al., 2020). Several biotechnological strategies could leverage these insights for agricultural applications. Exogenous application of key metabolites, for example, may serve as a chemical priming approach capable of inducing beneficial epigenetic memory without the need for genetic modification. Alternatively, precise metabolic engineering using CRISPR technologies could reshape intracellular metabolite pools by targeting biosynthetic or catabolic enzymes, thereby redirecting metabolic flux toward essential substrates, such as SAM or acyl‐CoA, which promote stress‐adaptive epigenetic modifications. CRISPR‐based epigenome editing offers an additional avenue (Nakamura et al., 2021; Shin et al., 2022). By fusing deactivated Cas9 with specific epigenetic modifiers, chromatin marks can be selectively deposited or removed at defined genomic loci. Such targeted recruitment allows high local enzymatic activity that can counteract environmentally induced fluctuations in metabolite availability, ensuring stable maintenance of desired epigenetic states and mitigating undesirable PTMs generated by metabolic noise. These approaches highlight how leveraging the metabolic–epigenetic interplay provides a promising framework for engineering climate‐resilient crops.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

P.J.S. and J.H. conceived and wrote the manuscript. All authors have read and approved the contents of this paper.

Biographies

Hwang, J. and Seo, P.J. (2026). Linking cellular metabolism to chromatin modifications in plants. J. Integr. Plant Biol. 68: 2416–2430.