Grant: Team Grant: 4D Nucleome Transformative Collaborative Project

Disease and development are reflected in chromatin states and their interactions in regulatory space. As opposed to developmental processes, it is anticipated that the genetic and epigenetic predisposition in disease is based on subtle alterations in chromatin conformation. Translational studies of altered chromatin structure are currently hampered by inflexible technologies. Direct "chromatin conformation association studies" require methodology that is scalable, tunable, and robust to variable quality of biological materials. We have charted CpG methylation variation in high-resolution across hundreds of population samples and observe significant enrichment of allelic and non-allelic methylation variation correlations in genomic regions shown to directly interact by conventional chromatin conformation assays. Preliminary data also points to preferential location of informative CpGs at boundaries of regulatory regions. We now propose the generation of a resource and framework to utilize interacting differentially methylated regions (iDMRs) applicable in large-scale studies to assess phenotypic importance of chromatin looping variation. We leverage methodologies we developed for targeted bisulfite sequencing to allow very high-resolution analyses for iDMRs as well as a unique cellular panel of human mesenchymal stem cells and their differentiated derivatives where standardized reference epigenome maps are generated in parallel. The full spectrum of chromatin conformation variation ranging from inter-individual to developmental differences are represented in this dataset serving as the optimal platform to develop analytical approaches for iDMR discovery. Conventional approaches for detecting and disrupting chromatin conformation in same cells serve to benchmark iDMR specificity and sensitivity. The resource and methods developed here will pave the way for systematic interrogation of chromatin conformation in new areas of population health and complex disease risk.