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 impairments in brain function. Current treatment options are limited, primarily because of the difficulty of replacing lost neurons.

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

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

Changes in the epigenome

Two teams, one led by Magdalena Götz, Chair of Physiological Genomics at LMU, Director of the Stem Cell Center at Helmholtz Munich and Researcher at the SyNergy Cluster of Excellence, and the other led by Boyan Bonev at the Helmholtz Pioneer Campus, explored the molecular mechanisms at play when glial cells are converted into neurons by a single transcription factor.

The results are published in the journal Neuroscience of Nature.

The researchers focused on small chemical modifications to the epigenome. The epigenome helps control which genes are active in different cells at different times. For the first time, the teams showed how coordinated the rewiring of the epigenome is, thanks to a single transcription factor.

Using novel epigenome profiling methods, the researchers identified that a post-translational modification of the neurogenic reprogramming transcription factor Neurogenin2 has a profound impact on epigenetic rewiring and neuronal reprogramming. However, the transcription factor alone is not sufficient to reprogram glial cells.

The researchers made an important discovery by identifying a new protein, the transcriptional regulator YingYang1, as a key player in this process. YingYang1 is required to open chromatin for reprogramming, for which it interacts with the transcription factor.

“The YingYang1 protein is essential for the conversion of astrocytes into neurons,” says Götz. “These results are important for understanding and improving the reprogramming of glial cells into neurons, and thus bringing us closer to therapeutic solutions.”