Mendenhall, Eric M.Williamson, Kaylyn E.Reyon, DeepakZou, James Y.Ram, OrenJoung, J. KeithBernstein, Bradley2014-07-072013Mendenhall, Eric M., Kaylyn E. Williamson, Deepak Reyon, James Y. Zou, Oren Ram, J. Keith Joung, and Bradley E. Bernstein. 2013. “Locus-specific editing of histone modifications at endogenous enhancers using programmable TALE-LSD1 fusions.” Nature biotechnology 31 (12): 10.1038/nbt.2701. doi:10.1038/nbt.2701. http://dx.doi.org/10.1038/nbt.2701.1087-0156http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406682Mammalian gene regulation is dependent on tissue-specific enhancers that can act across large distances to influence transcriptional activity1-3. 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 variants4-11. However, these studies did not address the in vivo functions of the putative elements or their chromatin states and could 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 down-regulation 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.en-USJournal Article2014-07-0710.1038/nbt.2701