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2016 ; 167
(1
): 233-247.e17
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Editing DNA Methylation in the Mammalian Genome
#MMPMID27662091
Liu XS
; Wu H
; Ji X
; Stelzer Y
; Wu X
; Czauderna S
; Shu J
; Dadon D
; Young RA
; Jaenisch R
Cell
2016[Sep]; 167
(1
): 233-247.e17
PMID27662091
show ga
Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene
expression networks in many biological processes. However, investigation of the
functions of specific methylation events remains challenging. Here, we
demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9
(dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or
-Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused
activation or silencing, respectively, of an endogenous reporter. Targeted
demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1
induced BDNF expression in post-mitotic neurons or activated MyoD facilitating
reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo
methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and
interfered with DNA looping, causing altered gene expression in the neighboring
loop. Finally, we show that these tools can edit DNA methylation in mice,
demonstrating their wide utility for functional studies of epigenetic regulation.
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