Nature methodsOct 27, 2015

Precise gene control using CRISPR to turn off distant DNA switches

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Targeted epigenetic modification using dCas9-KRAB resulted in highly specific induction of H3K9 trimethylation at the HS2 enhancer.

dCas9-KRAB was directed to the HS2 enhancer, affecting gene expression regulation.
Induction of H3K9 trimethylation was observed specifically at the enhancer.
Decreased chromatin accessibility was noted for both the enhancer and its promoter targets.
Silencing of multiple globin genes occurred with minimal off-target changes in global gene expression.
Repression via dCas9-KRAB may specifically disrupt the activity of individual enhancers.

Simplified

Epigenome editing with the CRISPR (clustered, regularly interspaced, short palindromic repeats)-Cas9 platform is a promising technology for modulating gene expression to direct cell phenotype and to dissect the causal epigenetic mechanisms of gene regulation. Fusions of nuclease-inactive dCas9 to the Krüppel-associated box (KRAB) repressor (dCas9-KRAB) can silence target gene expression, but the genome-wide specificity and the extent of heterochromatin formation catalyzed by dCas9-KRAB are not known. We targeted dCas9-KRAB to the HS2 enhancer, a distal regulatory element that orchestrates the expression of multiple globin genes, and observed highly specific induction of H3K9 trimethylation (H3K9me3) at the enhancer and decreased chromatin accessibility of both the enhancer and its promoter targets. Targeted epigenetic modification of HS2 silenced the expression of multiple globin genes, with minimal off-target changes in global gene expression. These results demonstrate that repression mediated by dCas9-KRAB is sufficiently specific to disrupt the activity of individual enhancers via local modification of the epigenome.

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Precise gene control using CRISPR to turn off distant DNA switches

Abstract

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