How Dual Epigenetic Guardians Preserve Neuronal Identity and Prevent Neurological Disorders

Neurons are highly specialized cells vital for brain function, and maintaining their identity throughout life is crucial for cognitive health. Recent research has uncovered the cooperative roles of two key enzymes, KDM1A and KDM5C, acting as epigenetic guardians that ensure neuronal stability. These enzymes work together to silence genes inappropriate for neurons and keep necessary gene expressions active, thereby preserving neuronal identity.

In a study published in Cell Reports, scientists from the Transcriptional and Epigenetic Mechanisms of Neuronal Plasticity laboratory, led by Ángel Barco at the Institute for Neurosciences (CSIC and UMH), explored what happens when these enzymes are absent. Using a mouse model where the KDM1A and KDM5C genes were simultaneously deleted in adult brain neurons, they observed significant changes. The loss of both enzymes resulted in abnormal accumulation of the epigenetic mark H3K4me3, usually associated with active genes, at regions meant to remain inactive in neurons. This disruption altered the three-dimensional structure of the neuronal genome and increased neuronal excitability, leading to cognitive and behavioral impairments such as deficits in memory, learning, and anxiety regulation.

The findings suggest that the joint action of KDM1A and KDM5C is more than the sum of their individual effects, highlighting their critical role in chromatin organization and neuronal gene regulation. Importantly, mutations in these genes are linked to intellectual disabilities and neurological disorders in humans, making this research vital for understanding the biological mechanisms underlying such conditions. The study paves the way for future investigations into therapeutic strategies targeting epigenetic regulation to treat or prevent neurological diseases.

This comprehensive study utilized genetics, molecular biology, electrophysiology, advanced microscopy, behavioral testing, and genomic analysis to uncover how epigenetic misregulation can contribute to neural dysfunction. Overall, these insights deepen our understanding of neuronal stability and offer potential avenues for intervention in neurological disorders related to epigenetic deregulation.