Novel role of non-coding RNAs in regulating genomic DNA methylation

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Through the advent of genomic sequencing it was revealed that the human genome is unique in that 98.5% encodes for non-protein coding DNA. Approximately 75% of the human genome is transcribed into non-coding RNA (ncRNAs) that do not code for proteins. Since this discovery one of the main questions has been, is there a functionally significant role that ncRNAs play in our cells?It is becoming clear that several ncRNA hold functional roles, acting as regulators of cell identity, and tissue homeostasis. In recent years, mapping and functional characterisation of ncRNAs, as well as RNA-binding proteins (RBPs) has increased. Research has shown there to be great potential for RNA in virtually all elements of cell biology relating to health and disease. Therefore, further investigation into non-coding RNAs has the potential to aid in a more comprehensive understanding of pathways relating to genomic stability, cell cycle control, and cell differentiation. Thus, ncRNA represents an unexploited therapeutic target for reprogramming applications and aging-related diseases. Recent studies have indicated that ncRNAs are involved in regulating epigenetic modifications such as, altering the processing of cytoplasmic mRNA, modulating chromatin function, and methylation of genomic DNA. Ultimately these functions affect gene expression and cell function. The epigenetic regulation of DNA methylation is dynamic and changes in response to environmental stressors. Upon the development of diseases such as, cancer and during biological processes such as, ageing DNA methylation patterns can undergo aberrant changes resulting in the incorrect expression of genes. Hence why an understanding of the fundamental regulatory mechanisms behind how DNA methylation is coordinated is important. This project has been set out to focus primarily on the effects of the lncRNA, CCDC26, on DNA methylation changes in the human genome. It has been demonstrated by the Kanhere group that CCDC26 binds to the enzyme DNA methyltransferase (DNMT1) which is known for catalysing and maintaining methylation of genomic DNA. CRISPR-Cas9 mediated removal of CCDC26 showed the effects of inhibiting the binding of DNMT1 to genomic DNA, resulting in hypomethylation, reduction in genomic stability and subsequently leading to increase cell death (Jones et al., 2021). This project aims to further elucidate these findings, with the goals of gaining a comprehensive understanding of the mechanisms behind ncRNA:DNMT1 interactions, helping us to speculate the role and functional significance of this interplay in ageing and development of disease. This work will be achieved through molecular and cell biology approaches to investigate the molecular mechanisms governing ncRNA mediated regulation of DNA methylation. As well as employment of modern technologies such as transcriptomics and CRISPR-Cas9 mediated genomic engineering. The aim of this project is to better characterise the functional significance of ncRNA, CCDC26, through methods that can be applied within the wider field of ncRNA research. By expanding our knowledge of ncRNAs and their association with epigenetic regulation in health and disease, there is future potential for ncRNAs to be used in clinical setting as prognostic or diagnostic biomarkers, as well as targets for novel therapies. Jones, R., Wijesinghe, S., Wilson, C., Halsall, J., Liloglou, T., & Kanhere, A. (2021). A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1. iScience, 24(4), 102273. doi:10.1016/j.isci.2021.102273