Genetics and Epigenetics in Neurodevelopmental and Neurodegenerative Disorders

The functional integrity of the central nervous system (CNS) is shaped by its genomic and epigenomic architecture, which acts as a dynamic interface between intrinsic cellular programs and environmental exposures (e.g., stress, toxins) to regulate gene expression. Beyond genetic variation, epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs, provide critical insights into neuronal biology and play crucial roles in contributing to the etiopathogenesis of several CNS disorders. For instance, epigenetic mechanisms tightly regulate chronic neuroinflammation and neuropathic pain. Aberrant modifications, particularly in glial cells (microglia and astrocytes), drive inflammation by affecting cytokine gene promoters (e.g., TNF-α). Early life and likely previous generations experiences inducing stable epigenetic marks (even through generations) may confer long-term risk or resilience to neuropathology. Epigenetic dysregulation spans the clinical spectrum, linking monogenetic neurodevelopmental disorders (e.g., Fragile X syndrome) to the age-related proteinaceous accumulation occurring in neurodegenerative disorders (e.g., Alzheimer’s or Parkinson's or other diseases).The main challenge in neuroepigenomics is translating discoveries into precision medicine protocols due to the brain's cellular heterogeneity and the Blood-Brain Barrier (BBB), which impedes targeted delivery. Thus, research efforts focus on overcoming these hurdles. A key focus is identifying the specific epigenetic signatures (DNA methylation, histone marks) that shift glial cells, particularly microglia, from a homeostatic state to a detrimental, pro-inflammatory phenotype. Non-coding RNAs (ncRNAs), such as lncRNAs, miRNAs, and circRNAs, are critical regulators of neuroinflammation and may represent highly specific therapeutic targets.To overcome cellular heterogeneity and resolve disease-specific signals, single-cell multi-omics coupled with state-of-the-art computational pipelines, including AI-based methods, can deliver granular, cell-type–resolved profiles. These approaches may also enable the discovery of non-invasive epigenetic biomarkers in accessible tissues. Therapeutic strategies should move from broad inhibitors to highly selective, third-generation enzyme modulators and ncRNA-directed interventions (e.g., antisense oligonucleotides), as well as precision gene-editing platforms such as CRISPR/Cas9. Importantly, cerebral organoids represent powerful 3D stem-cell–derived models recapitulating key aspects of brain cellular complexity, thus providing a powerful preclinical system to interrogate cell-type–specific epigenetic changes, screen targeted compounds, and evaluate novel delivery modalities in vitro.This Research Topic invites expert submissions focused on mechanistic depth and translational feasibility within the Neuroinflammation and Neuropathy section, structured around four core themes:• Molecular Mechanism and Epigenetics of Neuronal Cell Programming: exploration of epigenetic markers and mechanisms influencing neuron biology.• Nc-RNA Regulatory Networks and Inflammation: Molecular studies on post-transcriptional mechanisms modulating inflammatory mediators (e.g. NLRP3 inflammasome), highlighting a causal link to neuronal damage.• Non-invasive cell-type specific or circulating epigenomic profiling for biomarker discovery: application of innovative methodological and computational approaches (including single-cell multi-omics and AI approaches) to identify reliable epigenetic biomarkers of neurological diseases• Translational Epigenetic and Genetic Interventions: Preclinical evaluation of highly specific epigenetic enzyme inhibitors or ncRNA-based therapeutics designed to attenuate neuroinflammation in reliable disease models (including brain organoids).Acceptable Manuscript Types: Authors are encouraged to submit Original Research Articles, Systematic Review/Mini Review, Technical Note/Methods Article, and Perspective/Opinion/Commentary submissions. All manuscripts must adhere to rigorous peer-review standards. Topic editors: Valerio Caputo, Dariusz Stępkowski, Federica Centofanti Source: https://www.frontiersin.org/research-topics/75390/genetics-and-epigenetics-in-neurodevelopmental-and-neurodegenerative-disorders