Aging, Environment, & DiseaseDevelopmental Biology & Stem CellsDNA Methylation and Hydroxymethylation

The Same, Only Different: DNA Methylation Dynamics in the Human Genome

DNA methylation dynamicsDNA methylation is one of the most common, and most studied, epigenetic modifications.  DNA methylation plays a central role in the development and differentiation of mammalian cells, and when DNA methylation is misregulated, it can lead to many different types of human diseases, including cancer and neurological disorders.  DNA methylation, also known as 5-methylcytosine (5-mC), occurs primarily in CpG contexts, and in the human genome ~70-80% of cytosines in CpG dinucleotides are methylated.  While it is well established that the majority of CpG sites in our cells are methylated, the dynamics of how these methylation patterns change during cellular development, differentiation, and disease progression remain unclear.  A recent report in Nature led by the laboratory of Dr. Alexander Meissner at the Harvard Department of Stem Cell & Regenerative Biology and the Broad Institute of MIT and Harvard investigated DNA methylation dynamics in 30 different human cell and tissue types by performing whole-genome bisulfite sequencing (WGBS) coupled with complex bioinformatics and statistical analyses – and they found some very interesting results.

The researchers analyzed 42 different WGBS data sets, which consisted of 30 different normal and disease human cell and tissue types, including human embryonic stem (ES) cells and ES cell-derived cells, primary human cells, cells that had been in culture for long periods of time, and cells from human disease conditions such as cancer.  Using relatively stringent criteria for changes in DNA methylation (≥ 30% difference in methylation levels), and focusing on the “developmental” sample set (which excluded long-term cultured cells and the disease state cells), the authors identified ~5.6 million “dynamic” CpG sites in the human genome, which is only 21.8% of the total autosomal CpG sites investigated.  This means that the DNA methylation status for the remaining ~80% of the CpG sites in the human genome is pretty static and does not change significantly between different tissue types or developmental states.  Of these highly dynamic differentially methylated regions (DMRs), most of them (~70%) show high levels of methylation, and only very few (~2%) have low levels of DNA methylation, suggesting that CpG sites that are already methylated generally show the most dynamic changes, rather than normally unmethylated sites becoming methylated in some cases.

The DMRs often appear within genes or in genetic regulatory regions such as enhancers, which is consistent with these sites being important for driving cellular differentiation and cell fate decisions.  About half of the DMRs overlap at least one transcription factor binding site, and nearly two-thirds of the DMRs are localized to at least one gene coding region or gene regulatory element.  The authors also observed that there was a significant enrichment of single nucleotide polymorphisms (SNPs) within the DMRs, suggesting that these regions are both genetically and epigenetically dynamic.  Furthermore, tissue-specific DMRs were enriched for the corresponding tissue-specific SNPs.  For example, genomic regions with fetal heart-specific DMRs are also enriched for cardiovascular disease related SNPs.

The authors conclude their report by suggesting that focusing on the DMRs that they have identified would be a useful approach for the future of human health diagnostics and disease prognostics.  What do you think of these results?  Are you surprised that DNA methylation levels are so stable over most of the human genome?

 

Ziller MJ, Gu H, Müller F, Donaghey J, Tsai LT, Kohlbacher O, De Jager PL, Rosen ED, Bennett DA, Bernstein BE, Gnirke A, & Meissner A (2013). Charting a dynamic DNA methylation landscape of the human genome. Nature, 500 (7463), 477-81 PMID: 23925113

http://www.ncbi.nlm.nih.gov/pubmed/23925113

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Kevin B.

Kevin B.

Kevin grew up in Northern California and has also spent several years living on the East Coast. When he is not in the lab, Kevin enjoys snowboarding, watching NFL games (and playing fantasy football!), spending time outdoors, and exploring Southern California.