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Targeted intragenic demethylation initiates chromatin rewiring for gene activation

By Yanjing V Liu, Mahmoud A. Bassal, Quy Xiao Xuan Lin, Chan-Shuo Wu, Junsu Kwon, Qiling Zhou, Hong Kee Tan, Alexander K. Ebralidze, Li Chai, Touati Benoukraf, Annalisa Di Ruscio, Daniel G Tenen

Posted 17 Jul 2020
bioRxiv DOI: 10.1101/2020.07.16.205922

Aberrant DNA methylation in the region surrounding the transcription start site is a hallmark of gene silencing in cancer. Currently approved demethylating agents lack specificity and exhibit high toxicity. Herein we show, using the p16 gene as an example, that targeted demethylation of the promoter-exon 1-intron 1 (PrExI) region initiates an epigenetic wave of local chromatin remodeling and distal long-range interactions, culminating in gene-locus specific activation. Through development of CRISPR-DiR (DNMT1-interacting RNA), in which ad hoc edited guides block methyltransferase activity in a locus-specific fashion, we demonstrate that demethylation is coupled to epigenetic and topological changes. These results suggest the existence of a specialized "demethylation firing center (DFC)" which can be switched on by an adaptable and selective RNA-mediated approach for locus-specific transcriptional activation. ### Competing Interest Statement The authors have declared no competing interest.

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