Under a microscope, it can be hard to tell the difference between any two neurons, the brain cells that store and process information. So scientists have turned to molecular methods to try to identify groups of neurons with different functions.
Now, Salk Institute and University of California San Diego scientists have, for the first time, profiled chemical modifications of DNA molecules in individual neurons, giving the most detailed information yet on what makes one brain cell different from its neighbor. This is a critical step in beginning to identify how many types of neurons exist, which has eluded neuroscientists but could lead to a dramatically better understanding about brain development and dysfunction. Each cell’s methylome — the pattern of chemical markers made up of methyl groups that stud its DNA — gave a distinct readout that helped the Salk team sort neurons into subtypes. The work appears in the journal Science on August 10, 2017.
“We think it’s pretty striking that we can tease apart a brain into individual cells, sequence their methylomes, and identify many new cell types along with their gene regulatory elements, the genetic switches that make these neurons distinct from each other,” says co-senior author Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and an investigator of the Howard Hughes Medical Institute.
In the past, to identify what sets different types of neurons apart from each other, researchers have studied levels of RNA molecules inside individual brain cells. But levels of RNA can rapidly change when a cell is exposed to new conditions, or even throughout the day. So the Salk team turned instead to the cells’ methylomes, which are generally stable throughout adulthood.
“Our research shows that we can clearly define neuronal types based on their methylomes,” says Margarita Behrens, a Salk senior staff-scientist and co-senior author of the new paper. “This opens up the possibility of understanding what makes two neurons — that sit in the same brain region and otherwise look similar — behave differently.”