A long intergenic non-coding RNA regulates nuclear localization of DNA methyl transferase-1

Rhian Jones,Susanne Wijesinghe,Claire Wilson,John Halsall,Triantafillos Liloglou,Aditi Kanhere

doi:10.1016/j.isci.2021.102273

Rhian Jones, Susanne Wijesinghe + Show 4 more

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https://doi.org/10.1016/j.isci.2021.102273

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Journal: iScience	Publication Date: Mar 5, 2021
Citations: 8	License type: cc-by

Affiliation: University of Birmingham, University of Liverpool

Abstract

SummaryDNA methyl transferase-1 or DNMT1 maintains DNA methylation in the genome and is important for regulating gene expression in cells. Aberrant changes in DNMT1 activity and DNA methylation are commonly observed in cancers and many other diseases. Recently, a number of long intergenic non-protein-coding RNAs or lincRNAs have been shown to play a role in regulating DNMT1 activity. CCDC26 is a nuclear lincRNA that is frequently mutated in cancers and is a hotbed for disease-associated single nucleotide changes. However, the functional mechanism of CCDC26 is not understood. Here, we show that this lincRNA is concentrated on the nuclear periphery. Strikingly, in the absence of CCDC26 lincRNA, DNMT1 is mis-located in the cytoplasm, and the genomic DNA is significantly hypomethylated. This is accompanied by double-stranded DNA breaks and increased cell death. These results point to a previously unrecognized mechanism of lincRNA-mediated subcellular localization of DNMT1 and regulation of DNA methylation.

Highlights

In the mammalian genome, DNA is often methylated at cytosines in CpG dinucleotides
Aberrant changes in DNA cytosine-5methyltransferase 1 (DNMT1) activity and DNA methylation are commonly observed in cancers and many other diseases
A number of long intergenic non-protein-coding RNAs or long intergenic non-coding RNA (lincRNA) have been shown to play a role in regulating DNMT1 activity

Summary

Introduction

DNA methylation is one of the important epigenetic modifications needed for transcriptional regulation of genes (Jaenisch and Bird, 2003). This modification plays a crucial role in many vital cellular processes such as heterochromatin formation, X-chromosomal inactivation, and genomic stability (Csankovszki et al, 2001; Nan et al, 1998; Watt and Molloy, 1988). DNMT3a, DNMT3b, and DNMT1 are DNA methyltransferases that are responsible for establishing and maintaining genomic methylation in cells (Lyko, 2018). DNMT3a and DNMT3b are primarily involved in establishing de novo DNA methylation patterns in the genome. Evidence suggests that during the replication process, DNMT1 interacts with histonemodifying enzymes such as histone deacetylase HDAC2 as well as histone methyltransferases, EZH2 and G9a (Esteve et al, 2006; Rountree et al, 2000; Wang et al, 2017)

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