Abstract
DNA methylation is the most widely-studied epigenetic modification, playing a critical role in the regulation of gene expression. Dysregulation of DNA methylation is implicated in the pathogenesis of numerous diseases. For example, aberrant DNA methylation in promoter regions of tumor-suppressor genes has been strongly associated with the development and progression of many different tumors. Accordingly, technologies designed to manipulate DNA methylation at specific genomic loci are very important, especially in the context of cancer therapy. Traditionally, epigenomic editing technologies have centered around zinc finger proteins (ZFP)- and transcription activator-like effector protein (TALE)-based targeting. More recently, however, the emergence of clustered regulatory interspaced short palindromic repeats (CRISPR)-deactivated Cas9 (dCas9)-based editing systems have shown to be a more specific and efficient method for the targeted manipulation of DNA methylation. Here, we describe the regulation of the DNA methylome, its significance in cancer and the current state of locus-specific editing technologies for altering DNA methylation.
Highlights
Cancer is one of the leading causes of mortality worldwide and constitutes a major public health burden, despite the continued emergence of novel therapeutic approaches and improved clinical management [1]
Much of the existing evidence regarding epigenetic aberrations in cancer are based on the initial events of tumorigenesis, whilst less is known about the epigenetic events that can lead to metastasis [5]
Epigenetic changes are postulated as having an important role in primary cancer cell progression, contributing to the acquisition of additional properties that are essential for cancer metastasis [2,7,8,9]
Summary
Cancer is one of the leading causes of mortality worldwide and constitutes a major public health burden, despite the continued emergence of novel therapeutic approaches and improved clinical management [1]. Primary tumor cells require additional changes for successful metastasis, as even though these tumor cells have acquired cancer-specific mutations, less than 0.01% of cells that enter the circulation are able to metastasize [3]. This notion is supported by extensive sequencing data which indicates that genetic mutations alone are insufficient for successful metastasis [6]. DNA methylation, alongside histone modifications and non-coding RNAs, is one of the major mechanisms of epigenetic regulation and has a well-established role in the pathogenesis of many diseases, including cancers [6]. We provide details of the published work in this field far, the targeted editing systems currently available, and the potential implications of successful methylation-editing in cancer therapy development
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