Chromatin and Transcriptomic Engineering in Neurological Disorders: Emerging Human Cellular Models and Translational Approaches

Chromatin and transcriptional regulators are critical in neuronal development, function, and plasticity by shaping how, when and, where genes are expressed. Recent advances in DNA-targeting technologies have enabled precise manipulation of chromatin states through direct modification of DNA and histone marks by chromatin editors, and of transcriptional regulation using engineered activators or repressors. While both approaches have the potential to modulate gene expression, they operate via distinct mechanisms with potentially different implications for therapeutic durability and reversibility. To complement these advances, it is important to also implement these technologies within cellular models that capture the complexity of heritable epigenetic processes and human-specific information for modeling and therapeutic development. Here, we highlight recent work that leveraged chromatin editing and transcriptional regulatory tools to model and potentially treat neurological disorders. We also discuss work in developing advanced cellular models of human neurological diseases and the challenges and limitations of such systems.