Key mechanisms identified for neuron regeneration

Neurological disorders, such as trauma, stroke, epilepsy, and various neurodegenerative diseases, often result in permanent loss of neurons, leading to significant impairment in brain function. Current treatment options are limited, largely due to the challenge of replacing lost neurons.

Direct neuronal reprogramming, a complex procedure that changes the function of one cell type to that of another, offers a promising strategy.

In cell culture and in living organisms, glial cells, the non-neuronal cells in the central nervous system, have been successfully transformed into functional neurons. However, the processes involved in this reprogramming are complex and require further understanding. This complexity poses a challenge, but also a motivation, for researchers in the fields of neuroscience and regenerative medicine.

Changes in the epigenome

Two teams, one led by Magdalena Götz, professor of physiological genomics at LMU, head of the Stem Cell Center department at Helmholtz in Munich and researcher in the SyNergy Cluster of Excellence, and the other led by Boyan Bonev at the Helmholtz Pioneer Campus, investigated the molecular mechanisms involved when glial cells are converted into neurons by a single transcription factor.

The findings are published in the journal Nature Neuroscience.

Specifically, the researchers focused on small chemical modifications in the epigenome. The epigenome helps control which genes are active at different times in different cells. For the first time, the teams have now shown how coordinated the rewiring of the epigenome is, caused by a single transcription factor.

Using novel methods in epigenome profiling, the researchers discovered that a posttranslational modification of the reprogramming neurogenic transcription factor Neurogenin2 has a profound impact on epigenetic rewiring and neuronal reprogramming. However, the transcription factor alone is not enough to reprogram glial cells.

In a major discovery, the researchers identified a new protein, the transcriptional regulator YingYang1, as a key player in this process. YingYang1 is required to open the chromatin for reprogramming, for which it interacts with the transcription factor.

“The protein YingYang1 is crucial for achieving the conversion of astrocytes to neurons,” Götz explains. “These findings are important for understanding and improving the reprogramming of glial cells into neurons, and thus bring us closer to therapeutic solutions.”