Glial Cells Reprogrammed to Neurons for Brain Repair

Summary: Researchers have discovered how glial cells can be reprogrammed into neurons through epigenetic modifications, offering hope for treating neurological disorders. This reprogramming involves complex molecular mechanisms, including the transcription factor Neurogenin2 and the newly identified protein YingYang1, which opens chromatin for reprogramming.

The study reveals how coordinated epigenome changes drive this process, potentially leading to new therapies for brain injury and neurodegenerative diseases.

Key Facts:

  1. Neuronal Reprogramming: Glial cells can be transformed into neurons via epigenetic modifications.
  2. Key Players: Neurogenin2 and YingYang1 are crucial for the reprogramming process.
  3. Therapeutic Potential: This discovery could lead to new treatments for brain disorders and injuries.

Source: LUM

Researchers at LMU and Helmholtz Munich have shown how glial cells are reprogrammed into neurons via epigenetic modifications.

Neurological disorders, such as trauma, stroke, epilepsy, and various neurodegenerative diseases, often lead to the permanent loss of neurons, causing significant impairments in 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 type of cell into another, offers a promising strategy.

This shows glial cells.
For the first time, the teams have now shown how coordinated the epigenome rewiring is, elicited by a single transcription factor. Credit: Neuroscience News

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 presents a challenge, but also a motivation, for researchers in the field of neuroscience and regenerative medicine.

Modifications in the epigenome

Two teams, one led by Magdalena Götz, Chair of Physiological Genomics at LMU, Head of the Stem Cell Center Department at Helmholtz Munich, and researcher in 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 to neurons by a single transcription factor. 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. For the first time, the teams have now shown how coordinated the epigenome rewiring is, elicited by a single transcription factor.

Using novel methods in epigenome profiling, the researchers identified that a posttranslational modification of the reprogramming neurogenic transcription factor Neurogenin2 profoundly impacts the epigenetic rewiring and neuronal reprogramming.

However, the transcription factor alone is not enough to reprogram the glial cells. In an important discovery, the researchers identified a novel protein, the transcriptional regulator YingYang1, as a key player in this process. YingYang1 is necessary to open up the chromatin for reprogramming, to which end it interacts with the transcription factor.

“The protein Ying Yang 1 is crucial for achieving the conversion from astrocytes to neurons,” explains Götz.

“These findings are important to understand and improve reprogramming of glial cells to neurons, and thus brings us closer to therapeutic solutions.”

About this neuroscience research news

Author: Constanze Drewlo
Source: LUM
Contact: Constanze Drewlo – LUM
Image: The image is credited to Neuroscience News

Original Research: Open access.
Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1” by Magdalena Götz et al. Nature Neuroscience


Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1

Direct neuronal reprogramming is a promising approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodeling and co-factors facilitating this process are unclear.

In this study, we combined single-cell multiomics with genome-wide profiling of three-dimensional nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming mediated by Neurogenin2 (Ngn2) and its phosphorylation-resistant form (PmutNgn2), respectively.

We show that Ngn2 drives multilayered chromatin remodeling at dynamic enhancer–gene interaction sites. PmutNgn2 leads to higher reprogramming efficiency and enhances epigenetic remodeling associated with neuronal maturation.

However, the differences in binding sites or downstream gene activation cannot fully explain this effect. Instead, we identified Yy1, a transcriptional co-factor recruited by direct interaction with Ngn2 to its target sites. Upon deletion of Yy1, activation of neuronal enhancers, genes and ultimately reprogramming are impaired without affecting Ngn2 binding.

Thus, our work highlights the key role of interactors of proneural factors in direct neuronal reprogramming.

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