Transcriptional mechanisms of proneural factors and REST in regulating neuronal reprogramming of astrocytes

Giacomo Masserdotti, Sebastien Gillotin, Bernd Sutor, Daniela Drechsel, Martin Irmler, Helle F Jørgensen, Steffen Sass, Fabian J Theis, Johannes Beckers, Benedikt Berninger, Francois Guillemot, Magdalena Götz

Research output: Contribution to journalArticlepeer-review

144 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)74-88
JournalCell Stem Cell
Volume17
Issue number1
Early online date25 Jun 2015
DOIs
Publication statusPublished - 2 Jul 2015

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