Human DNA methylomes at base resolution show widespread epigenomic differences

Abstract

Summary DNA cytosine methylation is a central epigenetic modification that plays essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of mRNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that they may utilize different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development.

Epigenetic trigger for tomato ripening

“…1c). These findings are consistent with studies of mammalian genes, where hypomethylation of gene-regulatory regions is commonly observed at sites of DNA-protein interaction 8 . Interestingly, the authors observe very little change in DNA methylation state on transposable elements during fruit maturation, in stark contrast to the novel developmental demethylation events recently reported in the endosperm and pollen of Arabidopsis, which occur mainly on transposable elements 9,10 .…”

Functional Human Oocytes Generated by Transfer of Polar Body Genomes

“…This process undergoes dynamic changes during and after fertilization reflecting developmental reprogramming (Canovas and Ross, 2016). Also, the establishment of stable ESCs is associated with major changes in methylation profiles as the genome reconfigures to the pluripotent state (Lister et al, 2009;Lister et al, 2011;Ma et al, 2014). To evaluate the normalcy of these changes, we conducted genome-wide DNA methylation analysis of PBNT1 and hESO-14 cell lines using high-coverage, base-resolution MethylCseq (Lister et al, 2009) Both lines showed similar levels of CG methylation, a difference of only 0.7% between PBNT1 (86.1%) and hESO-14 (85.4%), and non-CG methylation, a difference of only 0.4% between PBNT1 (1.3%) and hESO-14 (0.9%) ( Figure 3A and 3B).…”

DNA methylation and healthy human aging

“…Interestingly, this negative correlation is not upheld when comparing expression and DNA methylation for a specific gene across individuals (van Eijk et al ., 2012; Lam et al ., 2012; Gutierrez Arcelus et al ., 2013; Wagner et al ., 2014). Conversely, DNA methylation in the gene body is often positively associated with levels of gene expression (Lister et al ., 2009; Gutierrez Arcelus et al ., 2013). DNA methylation also functions to repress repetitive elements, such as Alu and LINE‐1, which are generally highly methylated in the human genome.…”