Locus-specific editing of histone modifications at endogenous enhancers

Eric M. Mendenhall, Kaylyn E. Williamson, Deepak Reyon, James Y. Zou, Oren Ram, J. Keith Joung, Bradley E. Bernstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

303 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)1133-1136
Number of pages4
JournalNature Biotechnology
Volume31
Issue number12
DOIs
StatePublished - Dec 2013
Externally publishedYes

Bibliographical note

Funding Information:
We thank members of the Bernstein laboratory and the Broad Institute’s Epigenomics Program and for constructive comments and criticisms. We thank N. Shoresh, S. Kadri, M. Guttman and M. Garber for assistance with analysis. This research was supported by the Howard Hughes Medical Institute (to B.E.B.), the National Human Genome Research Institute’s ENCODE Project U54 HG004570, U54 HG006991 (to B.E.B.), US National Institutes of Health Common Fund for Epigenomics U01 ES017155 (to B.E.B.), NIH Director’s Pioneer Award DP1 GM105378 (to J.K.J.), NIH P50 HG005550 (to J.K.J.), and the Jim and Ann Orr MGH Research Scholar Award (to J.K.J.).

Fingerprint

Dive into the research topics of 'Locus-specific editing of histone modifications at endogenous enhancers'. Together they form a unique fingerprint.

Cite this