Key mechanisms for neuronal regeneration identified

Neurological disorders such as trauma, stroke, epilepsy and various neurodegenerative diseases often lead to permanent loss of neurons, causing significant impairment of brain function. Current treatment options are limited, primarily due to the challenge 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 culture and in living organisms, glial cells – 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 presents a challenge but also a motivation for neuroscience and regenerative medicine researchers.

Modifications in the epigenome

Two teams, one led by Magdalena Götz, Chair of Physiological Genomics at LMU, head 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, investigated the molecular mechanisms at play when glial cells 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 in different cells at different times. The teams have now shown for the first time how coordinated the rewiring of the epigenome is, triggered by a single transcription factor.

Using new methods in epigenome profiling, the researchers found that post-translational modification of the reprogramming neurogenic transcription factor Neurogenin2 profoundly affects the epigenetic rewiring and reprogramming of neurons. However, the transcription factor alone is not sufficient to reprogram glial cells.

In an important discovery, the researchers identified a new protein, the transcriptional regulator YingYang1, as a key player in this process. YingYang1 is essential for opening chromatin for reprogramming, which occurs through interaction with a transcription factor.

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