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

DNA 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 which 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. Overall design: RNA-seq analysis of Wildtype and two CCDC26-null K562 lines