The Divergent 3D Genome Landscapes Of Aging And Neurodegenerative Mouse Models
Our cells contain a vast amount of DNA, which isn’t just a long string but is intricately folded into a complex three-dimensional (3D) structure within the nucleus. This 3D organization, known as chromatin structure or 3D genome organization, is vital for controlling which genes are active and for maintaining the stability of our genetic material. Neurons, in particular, need to preserve this precise arrangement throughout an organism’s life.
Recent research has shed light on how this crucial 3D structure changes during normal aging and in the context of neurodegenerative diseases. Scientists used a technique called Hi-C to map these 3D interactions in brain cells from different mouse models, including healthy adult, aged, and those mimicking neurodegenerative conditions like Alzheimer’s disease.
The study revealed that both aging and neurodegeneration lead to some common early changes, such as weaker interactions between different chromosomes, shifts in how active and inactive regions of the genome are organized (called A-to-B compartment shifts), and the loss of specific DNA loops that help regulate gene activity (architectural loops).
However, a key difference emerged: while aged neurons managed to largely maintain their “Topologically Associating Domains” (TADs)—regions of the genome that frequently interact with themselves—and short-range DNA interactions, the neurodegenerative models showed a significant reduction in these TADs, shorter loops, and a disorganized mixing of active and inactive genome compartments. These more severe disruptions were found to correlate with increased DNA damage.
These findings suggest that the aging process might create a “primed” state where the genome’s 3D organization begins to erode. This makes the brain more susceptible to further damage, and additional stressors, such as DNA damage, can then push it towards the more severe breakdown seen in neurodegenerative diseases. Understanding these distinct changes could be crucial for identifying early markers and developing new strategies to combat age-related brain disorders.
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