Two approaches reveal a new paradigm of ‘switchable or genetics-influenced allele-specific DNA methylation’ with potential in human disease

Abstract

Imprinted genes are vulnerable to environmental influences during early embryonic development, thereby contributing to the onset of disease in adulthood. Monoallelic methylation at several germline imprints has been reported as DNMT1-dependent. However, which of these two epigenetic attributes, DNMT1-dependence or allelic methylation, renders imprinted genes susceptible to environmental stressors has not been determined. Herein, we developed a new approach, referred to as NORED, to identify 2468 DNMT1-dependent DNA methylation patterns in the mouse genome. We further developed an algorithm based on a genetic variation-independent approach (referred to as MethylMosaic) to detect 2487 regions with bimodal methylation patterns. Two approaches identified 207 regions, including known imprinted germline allele-specific methylation patterns (ASMs), that were both NORED and MethylMosaic regions. Examination of methylation in four independent mouse embryonic stem cell lines shows that two regions identified by both NORED and MethylMosaic (Hcn2 and Park7) did not display parent-of-origin-dependent allelic methylation. In these four F1 hybrid cell lines, genetic variation in Cast allele at Hcn2 locus introduces a transcription factor binding site for MTF-1 that may predispose Cast allelic hypomethylation in a reciprocal cross with either C57 or 129 strains. In contrast, each allele of Hcn2 ASM in J1 inbred cell line and Park7 ASM in four F1 hybrid cell lines seems to exhibit similar propensity to be either hypo- or hypermethylated, suggesting a ‘random, switchable’ ASM. Together with published results, our data on ASMs prompted us to propose a hypothesis of regional ‘autosomal chromosome inactivation (ACI)’ that may control a subset of autosomal genes. Therefore, our results open a new avenue to understand monoallelic methylation and provide a rich resource of candidate genes to examine in environmental and nutritional exposure models.

Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci

“…2C). This is concordant with previous reports of biphasic (fully methylated and fully unmethylated) distributions of methylation in amplicons with high interindividual methylation variance and in PCR clones with bimodal methylation patterns (3, 31). Strikingly, allelic imbalances at SD-ASM loci could be traced to shifts in epiallele frequency spectra between alleles, typically shifts in relative frequencies of the fully methylated and fully unmethylated epialleles (Fig.…”

“…These “intermediate methylation” states reflect the relative frequencies of fully methylated and fully unmethylated epialleles corresponding to biphasic On/Off switching patterns (31) at regulatory loci marked with SD-ASM. Moreover, our analyses reveal that the SD-ASM is explainable by allele-specific switching patterns at thousands of heterozygous loci.…”

The conserved DNMT1 dependent methylation regions in human cells are vulnerable to environmental rotenone

“…For example, in a reciprocal cross between 129S1/SvlmJ and Cast/EiJ or between C57BL/6NJ and Cast/EiJ, the Cast allele with SNP C of Hcn2 ASM is always hypomethylated (i.e., independent of parental origin), whereas the 129 allele or the C57 allele with SNP A is always hypermethylated. Standing out of the previously appreciated sequence-dependent ASMs, a new paradigm of switchable ASMs that shows equal chances of either paternal or maternal allele to be methylated was revealed by our report (Martos et al 2017). Importantly, the switchable feature seems also conserved in the human genome.…”

“…In our recent work, we developed two approaches, no-rescued DMRs (NORED) and methylation mosaicity analyses (MethylMosaic), to identify numerous genomic loci bearing potential ASMs (Martos et al 2017). Both the known imprinted germline ASMs and newly identified ASMs are dependent on DNA methyltransferase 1 (DNMT1) .…”

Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

“…For example, deficiency of RNF2 increases autophagy induction (Xia et al, 2014). The imprinted GNAS gene can accelerate neuron death Martos et al, 2017;Plagge et al, 2008). To understand the biological roles of the differentially expressed genes (DEGs) upon rotenone treatment, we performed Gene Ontology (GO) enrichment analysis for biological process.…”