Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes
journal contributionposted on 2020-08-28, 13:11 authored by Giacomo Masserdotti, Sébastien Gillotin, Bernd Sutor, Daniela Drechsel, Martin Irmler, Helle F Jørgensen, Steffen Sass, Fabian J Theis, Johannes Beckers, Benedikt Berninger, François Guillemot, Magdalena Götz
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.
AnimalsAstrocytesBasic Helix-Loop-Helix Transcription FactorsCells, CulturedCellular ReprogrammingDNA-Binding ProteinsHumansMiceNerve Tissue ProteinsNeuronsPromoter Regions, GeneticRepressor ProteinsTranscription FactorsTranscription, GeneticGuillemot U117570528Developmental Biology06 Biological Sciences11 Medical and Health Sciences