Wednesday, August 30, 2017

Bringing the power of epigenomics to the T2DKP

Until recently, all of the results displayed in the Type 2 Diabetes Knowledge Portal (T2DKP) were based on genetic association data: the significance with which variants, or SNPs, occur in people’s genomes in conjunction with a disease or trait.

This information is hugely important for pinpointing regions of the genome that contribute to disease risk. It is now relatively straightforward to identify these regions, but it is still a large challenge to discover the mechanisms by which they act—especially for variants that are outside of coding sequences, without an obvious effect on the sequence of a particular protein. These non-coding variants, the most commonly seen in genetic association studies, are likely to affect tissue-specific gene regulation that could potentially be important to the disease process.

How can we overcome this challenge to find clues about the effects of these non-coding variants? Epigenomic data to the rescue!

Dr. Kyle Gaulton of the University of California at San Diego researches the transcriptional regulatory networks involved in type 2 diabetes by using epigenomic data in concert with genetic association data. He explains, "Regulatory elements control gene production and function, and are often highly specialized across cell and tissues and located far away from the genes they regulate. Molecular epigenomic hallmarks of gene regulation such as histone and DNA modifications, nucleosome depletion, chromatin conformation and DNA-protein interactions can pinpoint the precise genomic locations of regulatory elements. High-resolution epigenome maps of regulatory elements in pancreatic islets, liver, muscle, adipose and many other human tissues can then enable annotation of non-coding genetic variants and their potential gene regulatory functions. These maps are thus an invaluable component of determining how type 2 diabetes associated non-coding variants influence disease pathogenesis."

A recent paper from Dr. Gaulton and colleagues (Gaulton, KJ, et al. (2015) Nat Genet. 47:1415) illustrates the power of integrating these two data types. By combining information on transcription factor binding sites and tissue-specific chromatin states with genetic fine-mapping of T2D-associated loci, the authors elicidated the molecular mechanisms behind the effects of some T2D-associated variants, uncovering the role of the FOXA2 transcription factor in glucose homeostasis in T2D-relevant tissues.

Now, the T2DKP facilitates this type of analysis by presenting both genetic association and epigenomic data on Gene and Variant pages. We described the display of epigenomic data on Variant pages in a recent blog post. On Gene pages, epigenomic data are integrated into the LocusZoom display.

Locations of variants associated with T2D and chromatin states in pancreatic islets, across the SLC30A8 gene (partial view)


Below the plot of variant associations, chromatin states are displayed by default for the major T2D-relevant tissues. Using the pull-down menu at the top of the plot, you can choose from a diverse set to display other tissues and cell types. All of the details on how to use this interactive plot are included in our Gene Page guide.

This is only the first step for epigenomic data in the T2DKP. In the future, we plan to include additional types of epigenomic data that indicate chromatin accessibility and conformation. We will also add functionality; for example, for any given variant, you will be able to search for the tissues in which enhancer regions overlap the location of that variant.

As we actively develop this aspect of the T2DKP, we welcome your suggestions!

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