It’s easy to get overwhelmed by just how much data an epigenome can hold. It’s hard to decide exactly where to start studying DNA methylation. Assaying every CpG site in the genome just isn’t practical for most researchers and a lot of money is spent on obtaining uninformative data. “Owing to the relatively small fraction of genomic CpGs assayed or small sample cohorts, the question of what fraction of genomic CpGs changes its methylation state in the context of normal development as well as their regulatory context remains underexplored.”

Scientists from the Broad Institute of MIT and Harvard carried out an “in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types”. “When we asked, how many of them are changing, the answer was a very small fraction,” says senior author, Dr. Alexander Meissner. Relying on their own data and also putting the ENCODE data to good use they came across some interesting landmarks.

Here’s what they found:

There is “dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context”. That’s a much smaller number than most of us would have guessed given the global nature of epigenetics and now it looks there are some new areas in the genome for us to focus in on.

Most of these changes occur in regions that are distal to transcription start sites.

“These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription- factor-binding sites, which allow identification of key lineage-specific regulators”, and these regions would make great targets for new assays.

“Differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell- type-related diseases as determined by genome-wide association studies”, which makes perfect sense given the recent observance of both genome dependent and independent epigenetic inheritance.

Meissner concludes, “Importantly this allows us to improve our current approaches of mapping this important mark through more targeted strategies that still capture most of the dynamics.” So if you study the dynamics of methylation in development you should start refocusing all that research muscle away from catch all technologies and start focusing in on the biology, since “the results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70–80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation.”

Get a global but focused perspective in Nature, August 2013