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Nat Biotechnol DOI:10.1038/nbt.2701

Locus-specific editing of histone modifications at endogenous enhancers.

Publication TypeJournal Article
Year of Publication2013
AuthorsMendenhall, EM, Williamson, KE, Reyon, D, Zou, JY, Ram, O, J Joung, K, Bernstein, BE
JournalNat Biotechnol
Date Published2013 Dec
KeywordsChromatin, Enhancer Elements, Genetic, Histones, Mutagenesis, Site-Directed, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Regulatory Elements, Transcriptional

Mammalian gene regulation is dependent on tissue-specific enhancers that can act across large distances to influence transcriptional activity. Mapping experiments have identified hundreds of thousands of putative enhancers whose functionality is supported by cell type-specific chromatin signatures and striking enrichments for disease-associated sequence variants. However, these studies did not address the in vivo functions of the putative elements or their chromatin states and did not determine which genes, if any, a given enhancer regulates. Here we present a strategy to investigate endogenous regulatory elements by selectively altering their chromatin state using programmable reagents. Transcription activator-like (TAL) effector repeat domains fused to the LSD1 histone demethylase efficiently remove enhancer-associated chromatin modifications from target loci, without affecting control regions. We find that inactivation of enhancer chromatin by these fusion proteins frequently causes downregulation of proximal genes, revealing enhancer target genes. Our study demonstrates the potential of epigenome editing tools to characterize an important class of functional genomic elements.


Alternate JournalNat. Biotechnol.
PubMed ID24013198
PubMed Central IDPMC3858395
Grant ListDP1 GM105378 / GM / NIGMS NIH HHS / United States
U54 HG006991 / HG / NHGRI NIH HHS / United States
P50 HG005550 / HG / NHGRI NIH HHS / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
DP1 GM105378 / DP / NCCDPHP CDC HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States