An integrated regulatory network reveals pervasive cross-regulation among transcription and splicing factors (In collaboration with Meromit Singer and Lior Pachter from UC Berkeley)
DNA methylation is an important epigenetic marker associated with gene expression regulation in eukaryotes. While promoter methylation is relatively well characterized, the role of gene body DNA methylation remains unclear. Here we investigated the relationship of DNA methylation at intragenic exons with exon expression and histone modifications generated from a human fibroblast cell-line and primary B-cells. Consistent with previous work we found that gene body methylation is positively correlated with gene expression and that intragenic exons are higher methylated than their neighboring intronic environment. Intriguingly, we show that the overall elevated DNA methylation at exons relative to their surrounding introns is primarily a characteristic of silenced genes. These results were independent of the inclusion rate of the exons, suggesting a novel role for exon methylation that does not directly relate to active transcription or splicing processes. Furthermore, we observed a negative correlation between gene body exon methylation and the density of the majority of histone modifications. Specifically, we demonstrate that hypo-methylated exons have a characteristic histone code comprised of significantly high levels of histone markings, which are positively correlated with exon expression. Overall, our comprehensive analysis of the human exome supports the presence of a novel regulatory mechanism at hypo-methylated intragenic exons. In particular our results reveal a previously unrecognized diverse and complex role of the epigenetic landscape at exonic regions within the gene body.
Expressed and hypomethylated intragenic exons are significantly enriched with histone modifications. (a) Normalized histone modification densities at the bottom 20-th percentile of expression (left), the medium expression rates (middle) and the top 20-th percentile of expression (right). Bold lines mark averages across the 28 measured histone modifications for the hypomethylated (blue) and methylated (red) exons sets. Shaded regions mark one standard deviation. (b) The histone modification pattern of the four different exon groups: low expressed, methylated exons (LowE HighM), low expressed , hypomethylated exons (LowE, LowM) Highly expressed , methylated exons (HighE HighM) and Highly expressed, hypomethylated exons (HighE lowM) (c) Density of the different histone modifications at three exons located at the intragenic region of the highly expressed LAMA4 gene. The left and middle exons are methylated and the right exon is hypomethylated.