Abstract
BackgroundDNA methylation is a highly studied epigenetic signature that is associated with regulation of gene expression, whereby genes with high levels of promoter methylation are generally repressed. Genomic imprinting occurs when one of the parental alleles is methylated, i.e., when there is inherited allele-specific methylation (ASM). A special case of imprinting occurs during X chromosome inactivation in females, where one of the two X chromosomes is silenced, to achieve dosage compensation between the sexes. Another more widespread form of ASM is sequence dependent (SD-ASM), where ASM is linked to a nearby heterozygous single nucleotide polymorphism (SNP).ResultsWe developed a method to screen for genomic regions that exhibit loss or gain of ASM in samples from two conditions (treatments, diseases, etc.). The method relies on the availability of bisulfite sequencing data from multiple samples of the two conditions. We leverage other established computational methods to screen for these regions within a new R package called DAMEfinder. It calculates an ASM score for all CpG sites or pairs in the genome of each sample, and then quantifies the change in ASM between conditions. It then clusters nearby CpG sites with consistent change into regions. In the absence of SNP information, our method relies only on reads to quantify ASM. This novel ASM score compares favorably to current methods that also screen for ASM. Not only does it easily discern between imprinted and non-imprinted regions, but also females from males based on X chromosome inactivation. We also applied DAMEfinder to a colorectal cancer dataset and observed that colorectal cancer subtypes are distinguishable according to their ASM signature. We also re-discover known cases of loss of imprinting.ConclusionWe have designed DAMEfinder to detect regions of differential ASM (DAMEs), which is a more refined definition of differential methylation, and can therefore help in breaking down the complexity of DNA methylation and its influence in development and disease.
Highlights
DNA methylation is a highly studied epigenetic signature that is associated with regulation of gene expression, whereby genes with high levels of promoter methylation are generally repressed
We introduce DAMEfinder (Differential Allele-specific MEthylation finder), an R package [38] that consists of (i) a scoring function that reflects allele-specific methylation (ASM) for several samples; (ii) integration with limma [39] and bumphunter [40] to detect differentially allele-specific methylated regions (DAMEs); and (iii) accurate estimation of false discovery rates (FDR)
We demonstrate the ASM score and DAMEfinder on two real datasets, one based on targeted enrichment bisulfite sequencing (BS-seq), comparing normal colonic mucosa to cancerous colorectal lesions, and another on whole genome BS-seq (WGBS), comparing blood monocytes from healthy females and males
Summary
DNA methylation is a highly studied epigenetic signature that is associated with regulation of gene expression, whereby genes with high levels of promoter methylation are generally repressed. Imprinting occurs via allele-specific methylation (ASM), in which only the paternal or the maternal allele is methylated in all or most of the tissues of an individual [9]. This methylation asymmetry is conferred during gametogenesis in the parental germlines, or during early embryogenesis after fertilization, and will remain during the lifetime of the offspring [10]. A recent survey [11] reported 228 genes linked to imprinted control, and from those, 115 linked to imprinted regulation in human placenta. Disruption of imprinting in somatic cells has been implicated in the pathogenesis of different cancers, like loss of imprinting within the H19/IGF2 imprinting control region in colorectal cancer [13], and gain of imprinting at 11p15 in hepatocellular carcinoma [14]
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