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Nat Biotechnol. 2013 Dec;31(12):1137-42. doi: 10.1038/nbt.2726. Epub 2013 Oct 9.

Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins.

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1
1] Department of Pathology and Center for Cancer Research, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [2] Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts, USA. [3] Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA. [4].

Abstract

Genome-wide studies have defined cell type-specific patterns of DNA methylation that are important for regulating gene expression in both normal development and disease. However, determining the functional significance of specific methylation events remains challenging, owing to the lack of methods for removing such modifications in a targeted manner. Here we describe an approach for efficient targeted demethylation of specific CpGs in human cells using fusions of engineered transcription activator-like effector (TALE) repeat arrays and the TET1 hydroxylase catalytic domain. Using these TALE-TET1 fusions, we demonstrate that modification of critical methylated promoter CpG positions can lead to substantial increases in the expression of endogenous human genes. Our results delineate a strategy for understanding the functional significance of specific CpG methylation marks in the context of endogenous gene loci and validate programmable DNA demethylation reagents with potential utility for research and therapeutic applications.

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PMID:
24108092
PMCID:
PMC3858462
DOI:
10.1038/nbt.2726
[Indexed for MEDLINE]
Free PMC Article
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