Targeting and Editing DNA Methylation and Hydroxymethylation for Gene Therapy

DNA methylation and hydroxymethylation are two key epigenetic modifications increasingly regarded as viable targets for gene therapy. Dysregulation of these marks in specific regions of the genome, such as regulatory regions, alters the expression of genes in various human disease settings, including cancer, obesity, infectious diseases, and other biological processes such as stem cell reprogramming and aging. Here, we summarize recent approaches in editing DNA methylation and discuss the state-of-the-art epigenome engineering strategies aimed at reprogramming DNA methylation in specific genomic sequences for therapeutic purposes. In addition, we outline major challenges for the preclinical and clinical implementation of epigenome editors - particularly CRISPR-based epigenetic modifiers - including the optimization of epigenetic editors, co-effector requirements, the risk of off-target activity, and the obstacles associated with achieving efficient in vivo tissue-specific delivery.