Looking to get switched on to new uses of epigenetics in the clinic? Check out EpiSwitch™, a platform for developing chromatin conformation diagnostics. One of the biggest challenges in genetic medicine is disease heterogeneity, both in terms of getting a diagnosis and determining the best treatment course. Often, genetic changes can only account for a small fraction of clinical subtypes in disease outcomes, so researchers are looking to epigenetics to help explain more. Chromosome conformation capture (3C) technologies have proven very useful for understanding the 3D structure of chromatin. Some researchers believe that assaying chromatin conformation is a better way to understand regulatory changes, since it can be a closer correlate of gene expression than any one histone mark or DNA methylation.
In a recent paper, Oxford BioDynamics assessed the utility of 3C as a diagnostic tool using their EpiSwitch™ platform. EpiSwitch™ uses a proprietary 3C-based pipeline in three steps:
- Microarray screening of a large number of loci in a small number of samples
- Multiple rounds of biomarker evaluation through PCR on select loci in more and more patient samples
- Validation of the selected assays in a blinded cohort
The disorder they tested was Amyotrophic Lateral Sclerosis (ALS). ALS disease presentation and rate of progression are variable, meaning there is no standard for diagnosis. The symptoms of ALS mimic many other conditions, contributing to a problematic diagnostic delay. The study authors sought to identify ALS-specific chromatin conformation changes at relevant genes that could distinguish ALS patients from controls.
Here’s what they found:
- Using a custom CGH Agilent microarray (which uses SNPs to detect genomic rearrangements) they assessed 13,880 possible chromosome conformations across 308 loci in 3 ALS cases vs. 3 controls
- Chromatin conformations are detected as genomic rearrangements ligated together by the 3C process
- The candidate loci were selected based on a literature search of ALS-related immune genes
- 153 putative biomarkers showing significant differences were selected from the array and used for EpiSwitch™ PCR based-detection
- Multiple rounds of biomarker evaluation on an increasing number of patient samples were used to reduce the number of markers to an 8 loci signature
- Finally, the signature was run across a discovery set of 74 known case & control skin and blood samples, then in 16 blinded blood samples
- Sensitivity and specificity for ALS detection were 83% & 76% respectively in the 74 known samples, and 87% & 75% in the blinded cohort
The relatively high sensitivity and specificity of this assay suggests that chromatin conformation may be an important for ALS etiology, and could be a valuable diagnostic tool. 3C may also be useful in numerous other disorders with an epigenetic basis, for instance the authors previously showed that EpiSwitch could aid in treatment course decision in rheumatoid arthritis. Given these exciting results, we hope we’ve switched you on to the idea of chromatin conformation as a diagnostic tool.
Check out the full story at EBioMedicine, June 2018