Epitranscriptomic Remodeling of N6-Methyladenosine (m6A) RNA Marks in CRISPR-Edited Genomes: Emerging Implications for Off-Target Genetic Instability and Precision Gene Therapy

Abstract

With the advent of epitranscriptomics, there is the addition of a regulatory layer of control over gene expression which goes beyond DNA sequence and chromatin-based regulation and encompasses dynamic chemical RNA modification. Of these N6-methyladenosine (m6A) is the most common interior modification of eukaryotic messenger RNA (mRNA) and is crucial in maintaining RNA stability, splicing, nuclear export, and translational efficiency. M6A deposition, removal and functional interpretation are regulated by an extensive system of methyltransferases (writers), demethylases (erasers) and RNA-binding proteins (readers), which allow a rapid and reversible regulation of gene expression in response to cellular signals.

Simultaneously, the emergence of CRISPR-Cas genome editing technologies has transformed the field of molecular biology and provided a new opportunity in the field of precision gene therapy. Although significant focus has been placed on the conceptualization of off-target DNA mutation and genomic instability, the consequences of genome editing on RNA layers of control, and especially, the epitranscriptomic changes have not been fully investigated. Recent data indicate that, following the formation of CRISPR-induced DNA double-strand breaks and the ensuing activation of DNA damage response pathways, the global state of cells can be changed, with a potential impact on m6A deposition patterns, including: chromatin remodeling, transcriptional reprogramming, and stress signaling.

This review offers the highest possible idea of the m6A epitranscriptomic environment and its regulatory apparatus, and then a deeper discussion of CRISPR-Cas systems and the cellular reactions related to it. We make the mechanistic case of the interaction between genome editing and m6A remodelling, and how the transcriptional dynamics and RNA-binding protein activity perturbation can cause transcriptome-wide changes in m6A distribution. We also compare the existing methods of m6A modifications detection, their advantages, and shortcomings, and address their possibilities of use in CRISPR-based research.

Notably, we discuss the consequences of the CRISPR-based epitranscriptomic variability to precise gene therapy, in which unintended RNA-level regulatory alterations can influence treatment safety, efficacy and reproducibility. Combining the findings of RNA biology, genome engineering, and high-throughput sequencing technologies, this review highlights the importance of taking into consideration epitranscriptomic measurements in genome editing models. The interaction between the CRISPR systems and m6A regulation will need a better insight, as it will be the key to more precise and safer therapeutic approaches.

Keywords:

Epitranscriptomics, N6-methyladenosine (m6A), CRISPR-Cas9, Genome Editing, RNA Modification, Off-target Effects, DNA Damage Response, Precision Gene Therapy

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