Light‐Activation of DNA‐Methyltransferases

Abstract

, the central epigenetic mark of mammalian DNA, playsf undamental roles in chromatin regulation. 5mC is written onto genomes by DNAm ethyltransferases (DNMT), and perturbation of this process is an early event in carcinogenesis.H owever,s tudying 5mC functions is limited by the inability to control individual DNMTs with spatiotemporal resolution in vivo.W ereport light-control of DNMT catalysis by genetically encoding ap hotocaged cysteine as ac atalytic residue.T his enables translation of inactive DNMTs,their rapid activation by light-decaging,and subsequent monitoring of de novo DNAm ethylation. We providei nsights into how cancer-related DNMT mutations alter de novo methylation in vivo,a nd demonstrate local and tuneable cytosine methylation by light-controlled DNMTs fused to ap rogrammable transcription activator-like effector domain targeting pericentromeric satellite-3 DNA. We further study early events of transcriptome alterations upon DNMTcatalyzedcytosine methylation. Our study sets abasis to dissect the order and kinetics of diverse chromatin-associated events triggered by normal and aberrant DNAm ethylation.