In the latest show of the power of teamwork we see some of the biggest names in epigenetics join forces to unravel the mysteries of the methylome across different tissues, including the molecular cartographers who tackled the brain and the researchers who brought forth the predictive powers of Epigram.
The talented team from the Salk Institute and UCSD have used whole genome bisulfite sequencing to provide great new depths for tissue specificity. Here’s what they found using an integrated approach on 18 organs from 4 individuals:
- The methylome typically clusters by tissue not individual.
- Hypomethylation at differentially methylated regions (DMRs) correlates with tissue specificity.
- DMRs have a negative correlation with transcription the closer they get to transcriptional start site.
- Interestingly the strongest repressive effect is not in the gene’s promoter but when methylation is between 0.3–8.0 Kb downstream of the transcription start site.
- These intragenic DMRs are, surprisingly, not usually CpG islands or shores, but rather a unique feature termed undefined intragenic DMRs (uiDMRs).
- uiDMRs correlate best with transcription when marked by histone modifications.
- There is widespread and very functional:
- tissue specific CpG methylation.
- partially methylated domains.
- allele specific methylation and transcription.
- CpH isn’t a rare event that is restricted to a few tissues: it appears in many tissues and has a previously under-appreciated role in tissue specificity.
- New tissue specific characteristics of genes that escape X-chromosome inactivation.
At the moment this data set is the deepest look into the human methylome. It offers an integration of CpG and CpH methylation, associated chromatin modifications, haplotype resolved whole genome sequence, and transcriptional profiles. All across an an unprecedented amount of tissues.
Going Deep into The CpH Methylome
In the news release from the Salk institute first author Matthew Schultz shares that “The only place this had been observed before was in the brain, skeletal muscle, germ cells and stem cells. So, to see it in a variety of normal adult tissues was really exciting.” Co-first author Yupeng He shares the next question: “What would be interesting to do next is split out different cell types. The samples we have are heterogeneous mixtures of many cells.”
Ecker concludes that “We wanted to make a baseline assessment of what the epigenome, in particular DNA methylation, looks like in normal human organs. In the past, people have really thought the promoter or the upstream regions are where everything is happening. But we found that methylation changes that are most correlated with gene transcription are often in the downstream regions of the promoter. You could imagine that eventually, if someone is having a problem, a biopsy might not only look at characterizing the cells or genes, but the epigenome as well.”
Learn about the future of tissue specificity in Nature, June 2015.