Genome-wide tracking of dCas9-methyltransferase footprints

Christina Galonska, Jocelyn Charlton, Alexandra L. Mattei, Julie Donaghey, Kendell Clement, Hongcang Gu, Arman W. Mohammad, Elena K. Stamenova, Davide Cacchiarelli, Sven Klages, Bernd Timmermann, Tobias Cantz, Hans R. Schöler, Andreas Gnirke, Michael J. Ziller and Alexander Meissner ()
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Christina Galonska: Max Planck Institute for Molecular Genetics
Jocelyn Charlton: Max Planck Institute for Molecular Genetics
Alexandra L. Mattei: Max Planck Institute for Molecular Genetics
Julie Donaghey: Harvard University
Kendell Clement: Harvard University
Hongcang Gu: Broad Institute of MIT and Harvard
Arman W. Mohammad: Broad Institute of MIT and Harvard
Elena K. Stamenova: Broad Institute of MIT and Harvard
Davide Cacchiarelli: Broad Institute of MIT and Harvard
Sven Klages: Max Planck Institute for Molecular Genetics
Bernd Timmermann: Max Planck Institute for Molecular Genetics
Tobias Cantz: Hannover Medical School
Hans R. Schöler: Max Planck Institute for Molecular Biomedicine
Andreas Gnirke: Broad Institute of MIT and Harvard
Michael J. Ziller: Max Planck Institute of Psychiatry
Alexander Meissner: Max Planck Institute for Molecular Genetics

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract In normal mammalian development cytosine methylation is essential and is directed to specific regions of the genome. Despite notable advances through mapping its genome-wide distribution, studying the direct contribution of DNA methylation to gene and genome regulation has been limited by the lack of tools for its precise manipulation. Thus, combining the targeting capability of the CRISPR–Cas9 system with an epigenetic modifier has attracted interest in the scientific community. In contrast to profiling the genome-wide cleavage of a nuclease competent Cas9, tracing the global activity of a dead Cas9 (dCas9) methyltransferase fusion protein is challenging within a highly methylated genome. Here, we report the generation and use of an engineered, methylation depleted but maintenance competent mouse ES cell line and find surprisingly ubiquitous nuclear activity of dCas9-methyltransferases. Subsequent experiments in human somatic cells refine these observations and point to an important difference between genetic and epigenetic editing tools that require unique experimental considerations.

Date: 2018
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DOI: 10.1038/s41467-017-02708-5

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