Chromatin context-dependent effects of epigenetic drugs on CRISPR-Cas9 editing

The efficiency and outcome of CRISPR/Cas9 editing depends on the chromatin state at the cut site. It has been shown that changing the chromatin state can influence both the efficiency and repair outcome, and epigenetic drugs have been used to improve Cas9 editing. However, because the target protein...

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Vydáno v:	Nucleic acids research Ročník 52; číslo 15; s. 8815 - 8832
Hlavní autoři:	Schep, Ruben, Trauernicht, Max, Vergara, Xabier, Friskes, Anoek, Morris, Ben, Gregoricchio, Sebastian, Manzo, Stefano G, Zwart, Wilbert, Beijersbergen, Roderick L, Medema, René H, van Steensel, Bas
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Oxford University Press 27.08.2024
Témata:	Gene regulation, Chromatin and Epigenetics
ISSN:	0305-1048, 1362-4962, 1362-4962
On-line přístup:	Získat plný text
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Shrnutí:	The efficiency and outcome of CRISPR/Cas9 editing depends on the chromatin state at the cut site. It has been shown that changing the chromatin state can influence both the efficiency and repair outcome, and epigenetic drugs have been used to improve Cas9 editing. However, because the target proteins of these drugs are not homogeneously distributed across the genome, the efficacy of these drugs may be expected to vary from locus to locus. Here, we systematically analyzed this chromatin context-dependency for 160 epigenetic drugs. We used a human cell line with 19 stably integrated reporters to induce a double-stranded break in different chromatin environments. We then measured Cas9 editing efficiency and repair pathway usage by sequencing the mutational signatures. We identified 58 drugs that modulate Cas9 editing efficiency and/or repair outcome dependent on the local chromatin environment. For example, we find a subset of histone deacetylase inhibitors that improve Cas9 editing efficiency throughout all types of heterochromatin (e.g. PCI-24781), while others were only effective in euchromatin and H3K27me3-marked regions (e.g. apicidin). In summary, this study reveals that most epigenetic drugs alter CRISPR editing in a chromatin-dependent manner, and provides a resource to improve Cas9 editing more selectively at the desired location. Graphical Abstract Graphical Abstract
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The first three authors should be regarded as Joint First Authors.
ISSN:	0305-1048 1362-4962 1362-4962
DOI:	10.1093/nar/gkae570