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

Abstract

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.

Epigenetics in ovarian cancer

“…Alternatively, hypomethylation may lead to expression of normally silenced oncogenes. There is also evidence that methylation within the gene body, counter to previous thought, may also regulate gene expression [40]; gene body hypomethylation also exists [41]. In EOC, as in cancer generally, global hypomethylation is seen across all histotypes and is associated with increasing stage, grade and mortality [33,42,43].…”

Bioinformatic analysis of the prognostic value and potential regulatory network of FOXF1 in papillary thyroid cancer

“…Then, using available DNA methylation 450 k data in TCGA‐THCA, we checked whether FOXF1 expression was related to its DNA methylation status. The methylation of the CpG sites in a gene locus can negatively or positively regulate gene expression, depending on its positions (promoter or gene body) and position associated regulatory effects . Promoter hypermethylation might contribute to decreased transcription.…”

“…Promoter hypermethylation might contribute to decreased transcription. In comparison, gene body methylation might lead to enhanced transcription . In this study, we examined the methylation status of 57 CpG sites among 355 classical PTC tissues and 41 adjacent normal tissues within the FOXF1 gene locus (Figure ).…”

“…The methylation of the CpG sites in a gene locus can negatively or positively regulate gene expression, depending on its positions (promoter or gene body) and position associated regulatory effects. [23][24][25] Promoter hypermethylation might contribute to decreased transcription. In comparison, gene body methylation might lead to enhanced transcription.…”

“…In comparison, gene body methylation might lead to enhanced transcription. [23][24][25] In this study, we examined the methylation status of 57 CpG sites among 355 classical PTC tissues and 41 adjacent normal tissues within the FOXF1 gene locus ( Figure 5). To screen methylation related CpG sites, we used the following two criteria: (a) Significantly different methylation status, normal vs. tumor (Welch's t-test, p < .05); (b) the methylation status of the CpG site was at least weakly correlated with FOXF1 expression (|Pearson' r| ≥0.2) ( Figure 5).…”