This is a summary of Pereira, A., Diwakar, J., Masserdotti, G. et al. Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1. published in Nature Neuroscience (2024). https://doi.org/10.1038/s41593-024-01677-5

The challenge

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. The 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 for neuron replacement. In laboratory settings and 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 neuronal reprogramming, including the role of transcription factors and the epigenome, are complex and require further understanding. This complexity presents a challenge and motivation for researchers in neuroscience and regenerative medicine, which is why we set out to study the conversion at the molecular level.

Our approach

We focused on changes and modifications in the epigenome. We combined single-cell multiomics with genome-wide profiling of 3D nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming. We compared transcription factors with different reprogramming efficiencies to link epigenome remodeling with the outcome of mouse astrocyte-to-neuron reprogramming. We looked at the neurogenic activity of Ngn2 and its phosphorylation-resistant form (PmutNgn2).

Our findings

We identified that the phosphorylation-resistant form of the reprogramming neurogenic transcription factor Neurogenin2 profoundly improved the epigenetic rewiring and neuronal reprogramming. In addition, we found that one of the factors predominatly up-regualted by the phosphorylation-resistant form of Ngn2 proved to be an essential co-factor to reprogram the glial cells into neurons. This is the transcriptional regulator YingYang1 that is necessary to open up the chromatin for reprogramming, to which end it interacts with the transcription factor. The protein is crucial for achieving the conversion from astrocytes to neurons.

The implications

These findings are important to understand and improve the reprogramming of glial cells to neurons and thus bring us closer to therapeutic solutions.

Creating SyNergies

The study was led by Magdalena Götz, Head of the Stem Cell Center Department at Helmholtz Munich and the division of Physiological Genomics at the Biomedical Center, LMU, as well as Boyan Bonev from the Helmholtz Pioneer Campus. Within the SyNergy network, we will now explore this improved reprogramming paradigm in pathology in vivo, such as stroke or traumatic brain injury.