Metabolite Mediated Epigenetic Regulation in Cellular Differentiation

Anneke De Vries

doi:10.35841/aacbm-7.3.271

Mini Review - Journal of Cell Biology and Metabolism (2025) Volume 7, Issue 3

Metabolite Mediated Epigenetic Regulation in Cellular Differentiation

Anneke De Vries^*

Department of Molecular Medicine, Leiden Biomedical Center, Netherlands.

*Corresponding Author:: Anneke De Vries
Department of Molecular Medicine
Leiden Biomedical Center, Netherlands
E-mail: a.devries@molmed.nl

Received: 03-Jun-2025, Manuscript No. AACBM-25-166669; Editor assigned: 04-Jun-2025, PreQC No. AACBM-25-1666695(PQ); Reviewed: 18-Jun-2025, QC No AACBM-25-1666695; Revised: 21-Jun-2025, Manuscript No. AACBM-25-1666695(R); Published: 28-Jun-2025, DOI:10.35841/aacbm-7.3.271

Citation: De Vries A. Metabolite Mediated epigenetic regulation in cellular differentiatio. J Cell Biol Metab. 2025;7(3):271.

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Introduction

Cellular differentiation is a fundamental biological process by which unspecialized cells, such as embryonic stem cells or progenitor cells, acquire specialized functions and phenotypes. This transition is tightly regulated through complex gene expression programs, governed not only by transcription factors and signaling pathways but also by epigenetic mechanisms that influence chromatin structure and accessibility. Epigenetic regulation, including DNA methylation, histone modifications, and chromatin remodeling, ensures stable and heritable patterns of gene expression during differentiation [1]. Emerging research has revealed a profound interconnection between cellular metabolism and epigenetic regulation, where specific metabolites act as essential cofactors or substrates for chromatin-modifying enzymes. These metabolite-epigenetic interactions are increasingly recognized as critical modulators of cell fate decisions, and their dynamic regulation plays an essential role in coordinating metabolic states with developmental cues during differentiation [2].

A central concept in metabolite-mediated epigenetic control is that various chromatin-modifying enzymes depend directly on the availability of metabolic intermediates. These include S-adenosylmethionine (SAM), acetyl-CoA, nicotinamide adenine dinucleotide (NAD+), alpha-ketoglutarate (α-KG), succinate, fumarate, and flavin adenine dinucleotide (FAD), among others. The availability and intracellular concentration of these metabolites fluctuate in response to nutrient levels, oxygen tension, mitochondrial activity, and extracellular signals, effectively linking cellular metabolic states with epigenetic landscapes [3].

DNA and histone methylation are primarily controlled by enzymes that use SAM as a methyl donor. DNA methyltransferases (DNMTs) catalyze the transfer of methyl groups from SAM to cytosine residues, particularly at CpG dinucleotides, resulting in transcriptional repression of target genes. Similarly, histone methyltransferases (HMTs) utilize SAM to methylate specific lysine and arginine residues on histone tails, creating a diverse set of methyl marks that either activate or repress gene expression depending on context. During differentiation, precise changes in DNA and histone methylation are required for lineage-specific gene expression. Because SAM is synthesized from methionine in the one-carbon metabolic pathway, fluctuations in methionine availability, folate cycle activity, or enzymatic flux can influence methylation dynamics. This is particularly evident in early embryogenesis, where the epigenetic reprogramming of the genome coincides with dramatic changes in metabolic fluxes and nutrient sensing [4].

In contrast to methylation, histone acetylation is catalyzed by histone acetyltransferases (HATs) using acetyl-CoA as the acetyl group donor. Histone acetylation generally leads to an open chromatin structure and transcriptional activation. Acetyl-CoA is a central metabolite at the intersection of glycolysis, fatty acid oxidation, and the tricarboxylic acid (TCA) cycle, making it a metabolic node that integrates nutritional status with epigenetic regulation [5]. During differentiation, the levels and compartmentalization of acetyl-CoA can modulate HAT activity and alter histone acetylation patterns, influencing the transcription of genes critical for lineage specification. For example, in neural differentiation, a metabolic shift toward oxidative metabolism leads to increased acetyl-CoA production in the nucleus, enhancing histone acetylation at neurogenic loci. Similarly, mesenchymal stem cells exposed to adipogenic or osteogenic signals exhibit divergent acetyl-CoA fluxes that drive lineage-specific histone acetylation profiles, demonstrating how metabolism sculpts the epigenetic landscape to guide differentiation [6].

Histone deacetylation, the removal of acetyl groups from histones, is mediated by two major classes of enzymes: histone deacetylases (HDACs) and sirtuins. While classical HDACs rely on zinc ions for activity, sirtuins are NAD+-dependent deacetylases, making their function tightly linked to cellular redox and energy states. NAD+ levels fluctuate with mitochondrial activity and glycolytic flux, allowing sirtuins to serve as metabolic sensors that modulate gene expression through chromatin remodeling. During differentiation, NAD+-dependent regulation of histone and non-histone protein acetylation contributes to changes in transcriptional programs. For instance, SIRT1, a nuclear sirtuin, plays a role in the differentiation of embryonic stem cells and muscle progenitors by deacetylating transcription factors and histones in response to NAD+ availability [7].

Demethylation of DNA and histones is another key epigenetic process influenced by metabolic intermediates. Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine in DNA using α-KG as a cofactor, initiating the DNA demethylation process. Likewise, Jumonji C domain-containing histone demethylases (JmjC-KDMs) remove methyl groups from histones via an α-KG–dependent oxidative reaction. The activity of these demethylases can be modulated by the intracellular concentration of α-KG, as well as by the accumulation of competitive inhibitors such as succinate and fumarate. Thus, the balance of TCA cycle intermediates not only supports energy production but also directly modulates chromatin states. During hematopoietic differentiation, increased α-KG production promotes TET and JmjC activity, leading to epigenetic changes that activate genes necessary for lineage commitment. Conversely, mutations in isocitrate dehydrogenase (IDH) enzymes, which convert isocitrate to α-KG, result in the production of 2-hydroxyglutarate (2-HG), an oncometabolite that inhibits α-KG–dependent enzymes, leading to hypermethylation and blocked differentiation, as observed in certain leukemias [8].

Flavin adenine dinucleotide (FAD), another essential metabolite derived from riboflavin, serves as a cofactor for lysine-specific demethylase 1 (LSD1), a histone demethylase that removes methyl groups from mono- and dimethylated histone H3 lysine 4 and lysine 9. LSD1 activity is important for repressing or activating gene expression depending on its context within chromatin complexes. FAD availability can modulate LSD1 activity and, in turn, influence gene expression patterns that drive cellular differentiation. In adipocyte differentiation, LSD1 interacts with specific transcription factors and chromatin remodelers to repress anti-adipogenic genes and promote lineage progression, underscoring the nuanced roles of metabolite-dependent demethylases in fate determination [9].

Mitochondrial metabolism also plays a critical role in shaping the epigenetic landscape of differentiating cells. As cells commit to specific lineages, their mitochondrial content, dynamics, and function change to meet the specialized metabolic demands of differentiated states. These changes influence the generation of metabolic cofactors and the availability of oxygen, which can affect the activity of oxygen-sensitive epigenetic enzymes. For example, during the transition from pluripotency to differentiation, an increase in oxidative phosphorylation boosts the production of metabolites like α-KG and acetyl-CoA, thereby enhancing the activity of demethylases and acetyltransferases. Conversely, hypoxic conditions inhibit α-KG–dependent dioxygenases and can lead to hypermethylation and impaired differentiation. Thus, oxygen and nutrient availability in the cellular microenvironment add another layer of metabolic regulation to epigenetic remodeling.

In addition to enzymatic cofactors, metabolites can influence epigenetic states indirectly by altering the expression or localization of chromatin regulators. For example, changes in ATP levels can affect the activity of ATP-dependent chromatin remodeling complexes that reposition nucleosomes to regulate gene accessibility. Similarly, altered lipid metabolism can influence histone acylation, a modification similar to acetylation, with roles in gene regulation that are just beginning to be understood [10].

Conclusion

In conclusion, metabolites are not merely byproducts of cellular metabolism but act as critical regulators of epigenetic modifications that control gene expression and cell fate. The dynamic interplay between metabolic fluxes and chromatin-modifying enzymes orchestrates the precise transcriptional programs required for cellular differentiation. As our understanding of this metabolite-epigenetic interface deepens, new opportunities arise for diagnostic, therapeutic, and engineering applications across developmental biology, regenerative medicine, and oncology. By unraveling the metabolic underpinnings of epigenetic regulation, we gain powerful tools to influence cell behavior and unlock the full potential of cellular plasticity.