∆DNMT3B4-del Contributes to Aberrant DNA Methylation Patterns in Lung Tumorigenesis

Aberrant DNA methylation is a hallmark of cancer but mechanisms contributing to the abnormality remain elusive. Here, we report that most of lung cancer cell lines tested expressed predominantly ∆DNMT3B-del whereas normal bronchial epithelial cells expressed equal quantities of ∆DNMT3B and ∆DNMT3B-del. We demonstrate biological impacts of ∆DNMT3B4-del, a ∆DNMT3B-del isoform, in a transgenic mouse model. Expression of ∆DNMT3B4-del in the mouse lungs resulted in an increased global DNA hypomethylation, focal DNA hypermethylation, epithelial hyperplastia and tumor formation when challenged with a tobacco carcinogen. In patients with non-small cell lung cancer, 83% of the primary tumors expressed predominantly ∆DNMT3B-del. Our results demonstrate ∆DNMT3B4-del as a critical factor in developing aberrant DNA methylation during lung tumorigenesis. Methyl binding domain protein-enriched genome sequencing (MBD-Seq) approach was employed to analyze methylated DNA regions in the genomic DNA samples. We constructed 6 libraries of genomic DNA samples from mouse lung tissues including 3 from wild-type mice and 3 from the transgenic mice. Each group (wild type or transgenic), therefore, consisted of three biological replicates.