Under a microscope, it can be difficult to tell the difference between any two neurons, the cells in our brain responsible for storing and processing information. The mammalian brain contains many diverse neuronal types, yet the global medical community lacks single-cell epigenomic assays to identify and characterize them. Now, a study led by Salk Institute develops a method capable of profiling chemical modifications in DNA for individual neurons, allowing them to identify previously unknown neuronal subtypes. The team states their new technique is a critical step in identifying how many types of neurons exist, possibly leading to a dramatically better understanding of brain development and dysfunction. The study is published in the journal Science.
Previous studies show it is possible to use levels of RNA molecules inside individual brain cells to identify what sets different types of neurons apart from each other. However, levels of RNA can rapidly change when a cell is exposed to new conditions throughout the day. Therefore, the team turned instead to the cells’ methylomes, a set of epigenetic-based changes where a methyl group is added to the genome, generally thought to be stable throughout adulthood. The current study shows each cell’s methylome gave a distinct readout allowing them to sort neurons into previously unknown subtypes.
The current study isolates 3,377 neurons from the frontal cortex of mice and 2,784 neurons from the frontal cortex of a 25-year-old human. The lab then used a new method they recently developed called snmC-seq to sequence the methylomes of each cell. Results show neurons from the mouse frontal cortex clustered into 16 subtypes based on epigenetic methylation patterns, while neurons from the human frontal cortex were more diverse and formed 21 subtypes.
Data findings show inhibitory neurons, known to provide stop signals for messages in the brain, exhibited more conserved methylation patterns between mice and humans compared to excitatory neurons. The group states their study also identified unique human neuron subtypes never before defined, opening the door to a deeper understanding of what sets human brains apart from other animals. They go on to add their new technique also proffers the possibility of understanding what makes two apparently similar neurons sitting in the same brain region behave differently.
The team surmises they have developed a technique able to clearly define neuronal types based on their methylomes, identifying previously unknown neuronal subtypes. For the future, the researchers state they now plan to expand their methylome study to look at more parts of the central nervous system, as well as the brains of different species.
Source: Salk Institute
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