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Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers

Technologies that enable targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we describe a programmable, CRISPR-Cas9-based acetyltransferase consisting of the nuclease-null... Full description

Journal Title: Nature biotechnology 2015-05, Vol.33 (5), p.510-517
Main Author: Hilton, Isaac B
Other Authors: D'Ippolito, Anthony M , Vockley, Christopher M , Thakore, Pratiksha I , Crawford, Gregory E , Reddy, Timothy E , Gersbach, Charles A
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
RNA
Publisher: United States: Nature Publishing Group
ID: ISSN: 1087-0156
Link: https://www.ncbi.nlm.nih.gov/pubmed/25849900
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4430400
title: Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers
format: Article
creator:
  • Hilton, Isaac B
  • D'Ippolito, Anthony M
  • Vockley, Christopher M
  • Thakore, Pratiksha I
  • Crawford, Gregory E
  • Reddy, Timothy E
  • Gersbach, Charles A
subjects:
  • Acetyltransferases - genetics
  • Article
  • CRISPR-Cas Systems - genetics
  • Deoxyribonucleic acid
  • DNA
  • E1A-Associated p300 Protein - genetics
  • Enhancer Elements, Genetic
  • Epigenetic inheritance
  • Epigenomics - methods
  • Gene expression
  • Genetic engineering
  • Genetic research
  • Genotype & phenotype
  • HEK293 Cells
  • Humans
  • Innovations
  • Observations
  • Promoter Regions, Genetic
  • Proteins
  • Ribonucleic acid
  • RNA
  • RNA Editing - genetics
  • RNA, Guide - genetics
  • Transcriptional Activation
ispartof: Nature biotechnology, 2015-05, Vol.33 (5), p.510-517
description: Technologies that enable targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we describe a programmable, CRISPR-Cas9-based acetyltransferase consisting of the nuclease-null dCas9 protein fused to the catalytic core of the human acetyltransferase p300. The fusion protein catalyzes acetylation of histone H3 lysine 27 at its target sites, leading to robust transcriptional activation of target genes from promoters and both proximal and distal enhancers. Gene activation by the targeted acetyltransferase was highly specific across the genome. In contrast to previous dCas9-based activators, the acetyltransferase activates genes from enhancer regions and with an individual guide RNA. We also show that the core p300 domain can be fused to other programmable DNA-binding proteins. These results support targeted acetylation as a causal mechanism of transactivation and provide a robust tool for manipulating gene regulation.
language: eng
source:
identifier: ISSN: 1087-0156
fulltext: no_fulltext
issn:
  • 1087-0156
  • 1546-1696
url: Link


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titleEpigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers
creatorHilton, Isaac B ; D'Ippolito, Anthony M ; Vockley, Christopher M ; Thakore, Pratiksha I ; Crawford, Gregory E ; Reddy, Timothy E ; Gersbach, Charles A
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descriptionTechnologies that enable targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we describe a programmable, CRISPR-Cas9-based acetyltransferase consisting of the nuclease-null dCas9 protein fused to the catalytic core of the human acetyltransferase p300. The fusion protein catalyzes acetylation of histone H3 lysine 27 at its target sites, leading to robust transcriptional activation of target genes from promoters and both proximal and distal enhancers. Gene activation by the targeted acetyltransferase was highly specific across the genome. In contrast to previous dCas9-based activators, the acetyltransferase activates genes from enhancer regions and with an individual guide RNA. We also show that the core p300 domain can be fused to other programmable DNA-binding proteins. These results support targeted acetylation as a causal mechanism of transactivation and provide a robust tool for manipulating gene regulation.
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subjectAcetyltransferases - genetics ; Article ; CRISPR-Cas Systems - genetics ; Deoxyribonucleic acid ; DNA ; E1A-Associated p300 Protein - genetics ; Enhancer Elements, Genetic ; Epigenetic inheritance ; Epigenomics - methods ; Gene expression ; Genetic engineering ; Genetic research ; Genotype & phenotype ; HEK293 Cells ; Humans ; Innovations ; Observations ; Promoter Regions, Genetic ; Proteins ; Ribonucleic acid ; RNA ; RNA Editing - genetics ; RNA, Guide - genetics ; Transcriptional Activation
ispartofNature biotechnology, 2015-05, Vol.33 (5), p.510-517
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descriptionTechnologies that enable targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we describe a programmable, CRISPR-Cas9-based acetyltransferase consisting of the nuclease-null dCas9 protein fused to the catalytic core of the human acetyltransferase p300. The fusion protein catalyzes acetylation of histone H3 lysine 27 at its target sites, leading to robust transcriptional activation of target genes from promoters and both proximal and distal enhancers. Gene activation by the targeted acetyltransferase was highly specific across the genome. In contrast to previous dCas9-based activators, the acetyltransferase activates genes from enhancer regions and with an individual guide RNA. We also show that the core p300 domain can be fused to other programmable DNA-binding proteins. These results support targeted acetylation as a causal mechanism of transactivation and provide a robust tool for manipulating gene regulation.
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titleEpigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers
authorHilton, Isaac B ; D'Ippolito, Anthony M ; Vockley, Christopher M ; Thakore, Pratiksha I ; Crawford, Gregory E ; Reddy, Timothy E ; Gersbach, Charles A
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issn1087-0156
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abstractTechnologies that enable targeted manipulation of epigenetic marks could be used to precisely control cell phenotype or interrogate the relationship between the epigenome and transcriptional control. Here we describe a programmable, CRISPR-Cas9-based acetyltransferase consisting of the nuclease-null dCas9 protein fused to the catalytic core of the human acetyltransferase p300. The fusion protein catalyzes acetylation of histone H3 lysine 27 at its target sites, leading to robust transcriptional activation of target genes from promoters and both proximal and distal enhancers. Gene activation by the targeted acetyltransferase was highly specific across the genome. In contrast to previous dCas9-based activators, the acetyltransferase activates genes from enhancer regions and with an individual guide RNA. We also show that the core p300 domain can be fused to other programmable DNA-binding proteins. These results support targeted acetylation as a causal mechanism of transactivation and provide a robust tool for manipulating gene regulation.
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