Editing DNA methylation in the mammalian genome
By X. S. Liu, Hao Wu, X. Ji, Y. Stelzer, Xuebing Wu, Szymon Czauderna, Jian Shu, Daniela Dadon, Richard A. Young, R. Jaenisch. Cell, 2016
1,114 citations recorded by the source corpus.
SUMMARY 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.
Subfields: Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/c090112436a11c732da18be7f1c640acc266a6c6
How researchers see this paper
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In Genetics
In Molecular Biology
- Denes Hnisz
- Richard A. Young
- James E. Bradner
- Jian‐Kang Zhu
- Alexander Meissner
- Nina Bailly
- Alexandra L. Mattei
- Yi Zhang
Citations in the corpus
- Genome Editing—Principles and Applications for Functional Genomics Research and Crop Improvement (2017, background): “For example, in mammalian cells, CRISPR/dCas9 has been fused with DNA methyltransferase 3a (DNMT3a) and DNA demethylase (TET1) to induce DNA methylation or demethylation respectively in target regions (Liu et al., 2016).”
- DNA methylation: a historical perspective. (2022, positive): “These systems were designed to control transcription of reporter genes by methylating or demethylating their promoters [250].”
- Transcriptional Addiction in Cancer (2017, positive): “In glioma cells that harbor mutations in the IDH1 gene, hypermethylation of insulated neighborhood anchor sites occurs, which leads to loss of CTCF binding at those anchors and activation of oncogenes that were previously silent in the intact neighborhoods (Flavahan et al., 2016).”