Activation of stably silenced genes by recruitment of a synthetic de-methylating module

Wing Fuk Chan (), Hannah D. Coughlan, Yunshun Chen, Christine R. Keenan, Gordon K. Smyth, Andrew C. Perkins, Timothy M. Johanson and Rhys S. Allan ()
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Wing Fuk Chan: The Walter and Eliza Hall Institute of Medical Research
Hannah D. Coughlan: The Walter and Eliza Hall Institute of Medical Research
Yunshun Chen: The Walter and Eliza Hall Institute of Medical Research
Christine R. Keenan: The Walter and Eliza Hall Institute of Medical Research
Gordon K. Smyth: The Walter and Eliza Hall Institute of Medical Research
Andrew C. Perkins: Monash University
Timothy M. Johanson: The Walter and Eliza Hall Institute of Medical Research
Rhys S. Allan: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation of dCas9-based activation systems. To counter this, we create an improved activation system by coupling the catalytic domain of DNA demethylating enzyme TET1 with transcriptional activators (TETact). We show that TETact demethylation-coupled activation is able to induce transcription of suppressed genes, both individually and simultaneously in cells, and has utility across a number of cell types. Furthermore, we show that TETact can effectively reactivate embryonic haemoglobin genes in non-erythroid cells. We anticipate that TETact will expand the existing CRISPR toolbox and be valuable for functional studies, genetic screens and potential therapeutics.

Date: 2022
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DOI: 10.1038/s41467-022-33181-4

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