Last month, our journal club read Chromatin marks identify critical cell types for fine mapping complex trait variants which features authors representing several of the anchor stores in Boston's shopping mall of biotech (the Broad, Dana Farber, and Brigham and Women's).
I gather that the term chromatin marks means modifications to the histones and other DNA packaging molecules. I'm not sure if the term is also meant to include DNA modifications like methylation or the arrangement of DNA around the histones. In any case, these modifications form part of the eukaryotic regulatory system and data for them is becoming available from ENCODE and other sources.
The cool thing is, at heart, the paper is about a data transformation, specifically a join, a mapping across biological data types. GWAS data links variants at particular loci on the genome to phenotype, typically disease, with a genetic component. Chromatin marks are thought to play a major role in differentiation. Marks at specific loci are associated with cell type. So, now we have a mapping from disease-associated variants to cell type. To complete the loop, many diseases are already known to play out in specific cell types.
The circle could be navigated in either direction, using one type of information to corroborate another. Known affected cell types for a disease may be used to select weak GWAS hits that are likely to be causal or informative about the mechanisms at work. The same might be applied to cancer, maybe helping to guide the search for causal variants implicated in cancers of particular cell types.
The paper categorized GWAS hits associated with LDL cholesterol hyperlipidemia, arthritis, psychiatric disorders, and type-2 diabetes based on one chromatin mark, trimethylation of histone H3 at lysine 4 (H3K4me3), and found a nice enrichment for the expected cell types.
In bloody red are cell types with immune function, blue is brain tissue, yellow groups together adipose, musculoskeletal and endocrine cells, and GI cell types are in bilious green.
The Broad does a nice job of writing up the paper in their news section: Chromatin marks the spot in search for disease pathways.
Links
- Chromatin marks identify critical cell types for fine mapping complex trait variants Gosia Trynka, Cynthia Sandor, Buhm Han, Han Xu, Barbara E Stranger, X Shirley Liu & Soumya Raychaudhuri, Nature Genetics 2013
- The accessible chromatin landscape of the human genome, Thurman et al. Nature 2012
- Readout of chromatin marks by histone–binding modules Haitao Li, Sean D. Taverna, Alexander J. Ruthenburg, Dinshaw J. Patel & C. David Allis
- Scripts and data related to the paper
- ENCODE downloads at UCSC
- GWAS Catalog
- NIH Roadmap Epigenomics Mapping Consortium
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