Scientists have identified a crucial mechanism in mice that safeguards the unique identity of neurons, ensuring their proper function. This discovery, made by researchers at the Institute of Neurosciences (IN), a collaborative center of the Spanish National Research Council (CSIC) and the Miguel Hernández University of Elche (UMH), highlights the intricate epigenetic processes that maintain cellular specialization. The study was published in the esteemed journal Cell Reports.
The research focused on the interaction between two enzymes, KDM1A and KDM5C. These proteins act as "epigenetic guardians," working in tandem to silence genes that are not specific to neurons. By ensuring that only the correct genetic instructions are active, they preserve the neuron's specialized role within the complex neural network. Mutations in the genes encoding KDM1A and KDM5C have been previously linked to intellectual disability and other neurological disorders in humans, underscoring the critical role of epigenetics in maintaining neuronal function.
The study utilized a sophisticated mouse model where the genes responsible for producing KDM1A and KDM5C were simultaneously deactivated in adult brain neurons. This approach allowed the scientists to observe the consequences of losing epigenetic control in mature neurons. When both KDM1A and KDM5C are absent, neurons begin to express genes that are inappropriate for their type, disrupting critical cognitive functions such as memory and learning, and affecting the regulation of anxiety.
The researchers observed significant alterations in the neuron's epigenetic landscape, with numerous genomic regions accumulating epigenetic marks typically associated with active genes in areas that should remain silent. Furthermore, the three-dimensional structure of the neuronal genome became disorganized. These molecular changes translated into altered neuronal physiology, including increased excitability, which ultimately led to observable behavioral and cognitive impairments in the mice.
This groundbreaking work builds upon previous findings from the same laboratory, which had already established the individual importance of KDM1A in maintaining genome organization and preventing age-related deterioration, and KDM5C in preventing erroneous gene transcription and refining neuronal responses. The novelty of the current study lies in demonstrating the synergistic action of these two proteins in preserving neuronal identity. This research opens promising avenues for deeper understanding into the origins of certain brain diseases and the development of potential therapeutic strategies.