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Breakthrough method yields trove of neuronal subtypes and gene regulators

Researchers have discovered a trove of neuronal subtypes and gene regulators, using a new method they developed called snmC-seq…

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Researchers have discovered a trove of neuronal subtypes and gene regulators, using a new method they developed called snmC-seq, which allows for the discovery of subtypes based on their unique profiles of molecular switches that regulate gene expression within the cell, which then opens the door to potentially discovering changes in such profiles linked to brain disorders.

“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 Dr Joseph Ecker, professor and director of Salk’s Genomic Analysis Laboratory and an investigator of the Howard Hughes Medical Institute.

The new method profiles molecular changes to the DNA known as epigenetic regulation. This is accomplished by sequencing the neuronal genomes in a way that detects modified DNA, producing a signature called the methylome.  It turns out that each cell type has a unique methylome, even though the DNA itself is the same in every cell.

The team began their work on both mouse and human brains by focusing on the frontal cortex. They isolated 3,377 neurons from the frontal cortex of mice and 2,784 neurons from the frontal cortex of a deceased 25-year-old human. The researchers at the University of California San Diego then used a new method they recently developed called snmC-seq to sequence the methylomes of each cell. Unlike other cells in the body, neurons have two types of methylation, so the approach mapped both types—called CG methylation and non-CG methylation.

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In the frontal cortex, the researchers identified 16 neuronal subtypes in mice and 21 subtypes in humans. Neurons that slow down brain activity were found to share more regulatory elements across mice and humans than neurons that speed up brain activity. Some of the latter excitatory neuron types featured “superenhancer” regulators unique to humans. The greater diversity in neuron types found in humans reflects more complex neuronal development known to occur in the human brain, say the researchers.

“We know the human brain has approximately 86 billion neurons—give or take—but we really don’t know much about how many different kinds of cells there are, what their functions are, or what goes wrong at the cellular level in different diseases,” explained Andrea Beckel-Mitchener, chief of the National Insitute of Mental Health (NIMH) Functional Neurogenomics Program, which supports the study. “This work is a big leap forward in our quest to understand neuronal diversity, adding an important molecular dimension never before achieved.” 

The BRAIN Initiative is helping researchers find new ways to classify brain cells. Traditionally, scientists were limited to describing cells only by their shape, location, or their electrical properties. The new method profiles molecular changes to the DNA known as epigenetic  regulation. This is accomplished by sequencing the neuronal genomes in a way that detects modified DNA, producing a signature called the methylome.  It turns out that each cell type has a unique methylome, even though the DNA itself is the same in every cell.

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