Targeted removal of epigenetic barriers during transcriptional reprogramming

Valentin Baumann, Maximilian Wiesbeck, Christopher T. Breunig, Julia M. Braun, Anna Köferle, Jovica Ninkovic, Magdalena Götz and Stefan H. Stricker ()
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Valentin Baumann: Ludwig-Maximilian-Universitaet, BioMedical Center
Maximilian Wiesbeck: Ludwig-Maximilian-Universitaet, BioMedical Center
Christopher T. Breunig: Ludwig-Maximilian-Universitaet, BioMedical Center
Julia M. Braun: Ludwig-Maximilian-Universitaet, BioMedical Center
Anna Köferle: Ludwig-Maximilian-Universitaet, BioMedical Center
Jovica Ninkovic: German Research Center for Environmental Health
Magdalena Götz: Ludwig-Maximilian-Universität
Stefan H. Stricker: Ludwig-Maximilian-Universitaet, BioMedical Center

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Master transcription factors have the ability to direct and reverse cellular identities, and consequently their genes must be subject to particular transcriptional control. However, it is unclear which molecular processes are responsible for impeding their activation and safeguarding cellular identities. Here we show that the targeting of dCas9-VP64 to the promoter of the master transcription factor Sox1 results in strong transcript and protein up-regulation in neural progenitor cells (NPCs). This gene activation restores lost neuronal differentiation potential, which substantiates the role of Sox1 as a master transcription factor. However, despite efficient transactivator binding, major proportions of progenitor cells are unresponsive to the transactivating stimulus. By combining the transactivation domain with epigenome editing we find that among a series of euchromatic processes, the removal of DNA methylation (by dCas9-Tet1) has the highest potential to increase the proportion of cells activating foreign master transcription factors and thus breaking down cell identity barriers.

Date: 2019
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DOI: 10.1038/s41467-019-10146-8

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