期刊
NATURE BIOTECHNOLOGY
卷 31, 期 12, 页码 1133-+出版社
NATURE PORTFOLIO
DOI: 10.1038/nbt.2701
关键词
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资金
- Howard Hughes Medical Institute
- National Human Genome Research Institute's ENCODE Project [U54 HG004570, U54 HG006991]
- US National Institutes of Health Common Fund for Epigenomics [U01 ES017155]
- NIH [DP1 GM105378, P50 HG005550]
- Jim and Ann Orr MGH Research Scholar Award
Mammalian gene regulation is dependent on tissue-specific enhancers that can act across large distances to influence transcriptional activity(1-3). 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(4-11). 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.
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