Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes
| العنوان: | Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes |
|---|---|
| المؤلفون: | Benedikt Berninger, Sébastien Gillotin, Magdalena Götz, Helle F. Jørgensen, Johannes Beckers, Bernd Sutor, Giacomo Masserdotti, Daniela Drechsel, Martin Irmler, Steffen Sass, François Guillemot, Fabian J. Theis |
| المساهمون: | Apollo - University of Cambridge Repository |
| المصدر: | Cell Stem Cell 17, 74-88 (2015) Cell Stem Cell Masserdotti, G, Gillotin, S, Sutor, B, Drechsel, D, Irmler, M, Jørgensen, H F, Sass, S, Theis, F J, Beckers, J, Berninger, B, Guillemot, F & Götz, M 2015, ' Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes ', Cell Stem Cell, vol. 17, no. 1, pp. 74-88 . https://doi.org/10.1016/j.stem.2015.05.014Test |
| بيانات النشر: | Elsevier BV, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Transcription, Genetic, Repressor, Nerve Tissue Proteins, Cell fate determination, Biology, DNA-binding protein, Article, Mice, Glutamatergic, Basic Helix-Loop-Helix Transcription Factors, Genetics, Animals, Humans, Promoter Regions, Genetic, Transcription factor, Cells, Cultured, Neurons, Cell Biology, Cellular Reprogramming, Molecular biology, Cell biology, DNA-Binding Proteins, Repressor Proteins, ASCL1, Astrocytes, embryonic structures, Molecular Medicine, GABAergic, Reprogramming, Transcription Factors |
| الوصف: | Summary Direct lineage reprogramming induces dramatic shifts in cellular identity, employing poorly understood mechanisms. Recently, we demonstrated that expression of Neurog2 or Ascl1 in postnatal mouse astrocytes generates glutamatergic or GABAergic neurons. Here, we take advantage of this model to study dynamics of neuronal cell fate acquisition at the transcriptional level. We found that Neurog2 and Ascl1 rapidly elicited distinct neurogenic programs with only a small subset of shared target genes. Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co-expression with Insm1 was required for glutamatergic maturation. Cultured astrocytes gradually became refractory to reprogramming, in part by the repressor REST preventing Neurog2 from binding to the NeuroD4 promoter. Notably, in astrocytes refractory to Neurog2 activation, the underlying neurogenic program remained amenable to reprogramming by exogenous NeuroD4. Our findings support a model of temporal hierarchy for cell fate change during neuronal reprogramming. Graphical Abstract Highlights • Neurog2 and Ascl1 regulate largely non-overlapping neurogenic targets • A subset of genes is required and sufficient to convert astrocytes and fibroblasts • Neurog2 and REST compete for binding to the NeuroD4 promoter • REST deletion enhances Neurog2-mediated reprogramming in vitro Masserdotti et al. analyzed early transcriptional changes mediated by Neurog2 and Ascl1 during direct reprogramming of murine postnatal astrocytes into distinct neuronal subtypes in vitro. This led to the identification of shared downstream targets, including NeuroD4, capable of neuronal reprogramming of fibroblasts and human astrocytes, as well as mechanistic insight into how the repressor REST functions as a barrier in direct neuronal reprogramming. |
| وصف الملف: | application/pdf |
| تدمد: | 1934-5909 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3eef806a6b87786cd049d6bac50dd4eTest https://doi.org/10.1016/j.stem.2015.05.014Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c3eef806a6b87786cd049d6bac50dd4e |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19345909 |
|---|