Targeted removal of epigenetic barriers during transcriptional reprogramming.
Valentin Baumann, Maximilian Wiesbeck, Christopher T. Breunig, Julia M. Braun, Anna Köferle, Jovica Ninkovic, Magdalena Götz, Stefan H. Stricker.
Nature Communications, 2019 May 9;10(1):2119. doi: 10.1038/s41467-019-10146-8.
cited directly from the publication abstract:
Master transcription factors have the ability to direct and reverse cellular identities, andconsequently their genes must be subject to particular transcriptional control. However, it isunclear which molecular processes are responsible for impeding their activation and safe-guarding cellular identities. Here we show that the targeting of dCas9-VP64 to the promoterof the master transcription factor Sox1 results in strong transcript and protein up-regulation inneural progenitor cells (NPCs). This gene activation restores lost neuronal differentiationpotential, which substantiates the role of Sox1 as a master transcription factor. However,despite efficient transactivator binding, major proportions of progenitor cells are unrespon-sive to the transactivating stimulus. By combining the transactivation domain with epigenomeediting wefind that among a series of euchromatic processes, the removal of DNA methy-lation (by dCas9-Tet1) has the highest potential to increase the proportion of cells activatingforeign master transcription factors and thus breaking down cell identity barriers.