Choline and DNA methylation: impact across metabolic, oncogenic and neurodevelopmental disorders

Aberrant DNA methylation patterns are increasingly recognized as contributors to a wide range of conditions, including metabolic, oncogenic, and neurodevelopmental disorders. Nutritional factors, such as choline, can shape methylation potential via methyl group donation. The purpose of this narrative review is to synthesize current evidence on the DNA methylation landscapes underlying health and disease paradigms, with a focus on the role of choline as a compelling target for modulating epigenetic states. A comprehensive literature review search was conducted in PubMed to identify relevant studies, with additional articles retrieved from review papers. In models of metabolic-associated steatotic liver disease, choline deficiency yields perturbed methylation of genes involved in lipid metabolism and mitochondrial function, whereas supplementation restores methylation balance and improves metabolic outcomes. In hepatocellular carcinomas, choline modulates methylation of tumor suppressor genes and oncogenes, interacting with one-carbon metabolism enzymes and the Wnt/β-catenin pathway. During development, gestational choline supplementation induces long-lasting epigenetic changes across multiple systems, affecting genes involved in stress regulation, neurodevelopment, and metabolism. Postnatal choline supplementation can also induce epigenetic remodeling, mitigating established aberrant methylation patterns in adulthood. Across models, choline availability modulates the methylation status of key regulatory genes in a highly context-dependent manner, as it is capable of either increasing or decreasing DNA methylation depending on molecular targets, developmental stage, tissue type, and disease state in a sex-specific manner. Alterations in DNA methylation span a wide spectrum of health conditions and diseases, with choline being a potential nutritional modulator through its role as a methyl donor. However, these modulatory effects are not unidirectional as they show subtle variations with context-specificity, highlighting the importance of precision in clinical methyl donor interventions. Studies that comprehensively map DNA methylation patterns and aim to establish causality may serve as an important gateway to identify relevant biomarkers, optimize choline-based therapeutic strategies, and confer more precise epigenetic modulation with translational relevance. Role of choline in DNA methylation landscapes underlying health and disease. DNA methylation patterns are maintained by various enzymes: "writers" that add methyl groups (Me) to cytosine residues and “erasers” that remove these marks. Choline, via its metabolite betaine, supplies methyl groups to the methionine cycle, supporting synthesis of S-adenosylmethionine (SAM), the universal methyl donor. SAM is used for methylation reactions, such as DNA methylation, and is converted to S-adenosylhomocysteine (SAH). Changes in DNA methylation have been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), hepatocellular carcinoma (HCC), diabetes, obesity and metabolic dysfunction, neurodevelopment and brain function, prenatal alcohol exposure (PAE), stress dysregulation, and Wilson’s disease. Through gene-, tissue-, developmental stage-, and sex-specific mechanisms, choline-dependent methylation provides a dynamic, modifiable interface between the environment, gene regulation, and health outcomes