From Genes to Regulatory Logic: Redefining Mechanisms and Therapeutic Strategies in Brain Disorders

Brain disorders—including psychiatric, neurodevelopmental, and neurodegenerative conditions—arise from complex interactions between genetic architecture, environmental exposure, and developmental timing. Rather than isolated molecular lesions, these disorders reflect hierarchical misalignments in regulatory systems that coordinate gene expression, chromatin state, and neural network dynamics. Genes establish potential boundaries of regulation, while early environmental conditions and experiences reshape cis-regulatory element (CRE) accessibility, thereby redefining the brain’s transcriptional and circuit landscape. During sensitive developmental periods, transient external signals can become biologically encoded through stable regulatory modifications, creating enduring trajectories of vulnerability or resilience. Distinct disorders emerge when the same molecular components operate within divergent regulatory topologies—such as enhancer overactivation, promoter silencing, or insulation loss—producing disease-specific phenotypes. Advances in single-cell multi-omics data, clinical data and AI-based modeling now allow reconstruction of these hierarchical networks, enabling the prediction of regulatory vulnerability and identification of intervention points. This regulation-centric framework reframes brain disorders as dynamic failures of gene–environment coordination, highlighting early regulatory plasticity as both the origin of pathology and a window for preventive treatment.