Body-hypomethylated human genes harbor extensive intragenic transcriptional activity and are prone to cancer-associated dysregulation.

Genomic DNA methylation maps (methylomes) encode genetic and environmental effects as stable chemical modifications of DNA. Variations in DNA methylation, especially in regulatory regions such as promoters and enhancers, are known to affect numerous downstream processes. In contrast, most transcription units (gene bodies) in the human genome are thought to be heavily methylated. However, epigenetic reprogramming in cancer often involves gene body hypomethylation with consequences on gene expression. In this study, we focus on the relatively unexplored phenomenon that some gene bodies are devoid of DNA methylation under normal conditions. Utilizing nucleotide-resolution methylomes of diverse samples, we show that nearly 2000 human genes are commonly hypomethylated. Remarkably, these genes occupy highly specialized genomic, epigenomic, evolutionary and functional niches in our genomes. For example, hypomethylated genes tend to be short yet encode significantly more transcripts than expected based upon their lengths, include many genes involved in nucleosome and chromatin formation, and are extensively and significantly enriched for histone-tail modifications and transcription factor binding with particular relevance for cis-regulation. Furthermore, they are significantly more prone to cancer-associated hypomethylation and mutation. Consequently, gene body hypomethylation represents an additional layer of epigenetic regulatory complexity, with implications on cancer-associated epigenetic reprogramming.