Cracking the code

Scripps uncovers new transcription factor combos to reprogram skin cells into different neurons

Kelsey Kaustinen
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LA JOLLA, Calif.—In the latest advancement for cellular reprogramming technology, a team of researchers from The Scripps Research Institute have reported on the discovery of several new transcription codes for differentiating skin cells into multiple different types of neurons. Their work, detailed in a paper titled “Diverse reprogramming codes for neuronal identity,” was published in Nature.
The scientists developed and tested a set of two factor codes to determine which ones were capable of programming skin cells to become neurons instead, particularly ones that recreate neuronal shape and electrical excitability. They tested 598 pairs of transcription factors altogether, and found that more than 12 percent were capable of producing neurons. This provides researchers with 76 new codes for the production of neurons.
Equally encouraging was the behavior of what Dr. Kristin Baldwin, a professor at Scripps Research and senior author of the study, referred to as the “synthetic neurons”—the converted neurons began to grow synapses and attempt to communicate with each other in the span of just a couple weeks.
To determine whether the new codes would produce different variations of neurons, Sohyon Lee, a co-first author on this research and recent Ph.D. graduate at Scripps Research, and Dr. Rachel Tsunemoto, also co-first author, turned to the “outputs” of the codes they’d worked with using electrical recording methods as well as new sensitive sequencing methods. Tsunemoto was a researcher with Scripps Research and the University of California, San Diego, at the time of the study.
They discovered that each code did indeed result in neurons with different properties. As the authors reported in their abstract, “By comparing the transcriptomes of these induced neuronal cells (iN cells) with those of endogenous neurons, we define a ‘core’ cell-autonomous neuronal signature. The iN cells also exhibit diversity; each transcription factor pair produces iN cells with unique transcriptional patterns that can predict their pharmacological responses. By linking distinct transcription factor input ‘codes’ to defined transcriptional outputs, this study delineates cell-autonomous features of neuronal identity and diversity and expands the reprogramming toolbox to facilitate engineering of induced neurons with desired patterns of gene expression and related functional properties.”
Baldwin called the results “a big step forward in cellular reprogramming,” as the use of the transcription factor “codes” means scientists can generate the exact types of neurons they want ad nauseam. This is particularly momentous when it comes to neurons, since, as noted online by Baldwin’s lab, “[N]eurons are primarily generated at birth and are maintained without cell division for the life of an individual. Neurons do not divide and have not been shown to generate tumors, for unknown reasons. The inability to generate cell lines from neurons precludes a number of important studies including analyses of neuronal genomic stability in differentiation and disease, and has impeded the generation of appropriate in-vitro models of disease.” At present, researchers tend to rely on samples obtained via brain surgery, which only remain viable for a matter of hours.
According to Baldwin, this research comes on the heels of years of work by her lab and others around the world. Nobel laureate Shinya Yamanaka and Marius Wernig’s group at Stanford University demonstrated that using sets of three to four factors enabled the conversion of skin cells into pluripotent stem cells and straight into neurons, and Baldwin’s lab had proved that applying sets of two factors enabled them to produce specific neurons that respond to stimuli such as itchiness or pain. That work, published in Nature Neuroscience in November 2014, described how Baldwin’s lab converted skin cells into the neurons responsible for registering sensation. These neurons are normally found in clusters known as dorsal root ganglia along the outer spine, and are affected by spinal cord injury and linked with Friedrich’s ataxia. Recent research has also tied them to aging and autoimmune disease.
“The brain is incredibly complex, with thousands of different types of cells that are each involved in different diseases,” says Baldwin, who was senior author of the study. “The problem with understanding and treating the many disorders of the brain is that we cannot reproducibly produce the right types of brain cells. Now we have found more than 75 new ways to rapidly and reproducibly turn skin cells into neurons that we think will be much better representatives of different neurologic diseases than were previously available.”

Kelsey Kaustinen

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