Locus-specific editing of histone modifications at endogenous enhancers

• Published in: Nature biotechnology Vol. 31; no. 12; pp. 1133 - 1136
• Main Authors: Mendenhall, Eric M, Williamson, Kaylyn E, Reyon, Deepak, Zou, James Y, Ram, Oren, Joung, J Keith, Bernstein, Bradley E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2013; Nature Publishing Group
• Subjects: 631/1647/2210; 631/1647/2210/2212; 631/208/200; 631/337/100/2285; Agriculture; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cellular biology; Chromatin; Chromatin - genetics; Enhancer Elements, Genetic - genetics; Gene expression; Genetic aspects; Genetic regulation; Histones; Histones - genetics; Inactivation; letter; Life Sciences; Mammals; Mutagenesis, Site-Directed - methods; Physiological aspects; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Proteins; Reagents; Regulatory Elements, Transcriptional - genetics; United States
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.2701

The function of specific enhancers is studied using TAL effectors fused to a histone demethylase. Mammalian gene regulation is dependent on tissue-specific enhancers that can act across large distances to influence transcriptional activity 1 , 2 , 3 . 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 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 . 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.