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Rapid and reversible epigenome editing by endogenous chromatin regulators

Kirkland, Jacob G
Chory, Emma J
Husmann, Dylan
Calarco, Joseph P
Crabtree, Gerald R
Published in Nature communications. 2017, vol. 8, no. 1, 560
Abstract Understanding the causal link between epigenetic marks and gene regulation remains a central question in chromatin biology. To edit the epigenome we developed the FIRE-Cas9 system for rapid and reversible recruitment of endogenous chromatin regulators to specific genomic loci. We enhanced the dCas9-MS2 anchor for genome targeting with Fkbp/Frb dimerizing fusion proteins to allow chemical-induced proximity of a desired chromatin regulator. We find that mSWI/SNF (BAF) complex recruitment is sufficient to oppose Polycomb within minutes, leading to activation of bivalent gene transcription in mouse embryonic stem cells. Furthermore, Hp1/Suv39h1 heterochromatin complex recruitment to active promoters deposits H3K9me3 domains, resulting in gene silencing that can be reversed upon washout of the chemical dimerizer. This inducible recruitment strategy provides precise kinetic information to model epigenetic memory and plasticity. It is broadly applicable to mechanistic studies of chromatin in mammalian cells and is particularly suited to the analysis of endogenous multi-subunit chromatin regulator complexes.Understanding the link between epigenetic marks and gene regulation requires the development of new tools to directly manipulate chromatin. Here the authors demonstrate a Cas9-based system to recruit chromatin remodelers to loci of interest, allowing rapid, reversible manipulation of epigenetic states.
Keywords CRISPR-Cas SystemsChromatin/metabolismChromatin Assembly and DisassemblyEpigenesisGeneticGene EditingGene Expression RegulationGene SilencingHEK293 CellsHeterochromatin/metabolismHumansPolycomb-Group Proteins/metabolismPromoter RegionsGenetic
PMID: 28916764
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Article (Published version) (881 Kb) - public document Free access
Research group Régulation de la chromatine dans le développement du cerveau (1031)
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BRAUN, Simon et al. Rapid and reversible epigenome editing by endogenous chromatin regulators. In: Nature Communications, 2017, vol. 8, n° 1, p. 560. doi: 10.1038/s41467-017-00644-y

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Deposited on : 2021-09-08

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