Abstract
Motivation While promoter methylation is associated with reinforcing fundamental tissue identities, the methylation status of distant enhancers was shown by genome-wide association studies to be a powerful determinant of cell-state and cancer. With recent availability of long-reads that report on the methylation status of enhancer-promoter pairs on the same molecule, we hypothesized that probing these pairs on the single-molecule level may serve the basis for detection of rare cancerous transformations in a given cell population. We explore various analysis approaches for deconvolving cell-type mixtures based on their genome-wide enhancer-promoter methylation profiles.
Results To evaluate our hypothesis we examine long-read optical methylome data for the GM12787 cell line and myoblast cell lines from two donors. We identified over 100,000 enhancer-promoter pairs that co-exist on at least 30 individual DNA molecules per pair. We developed a detailed methodology for mixture deconvolution and applied it to estimate the proportional cell compositions in synthetic mixtures based on analyzing their enhancer-promoter pairwise methylation. We found our methodology to lead to very accurate estimates, outperforming our promoter-based deconvolutions. Moreover, we show that it can be generalized from deconvolving different cell types to subtle scenarios where one wishes to deconvolve different cell populations of the same cell-type.
Availability The code used in this work to analyze single-molecule Bionano Genomics optical maps is available via the GitHub repository https://github.com/ebensteinLab/Single_molecule_methylation_in_EP.
Contact uv{at}post.tau.ac.il (Y.E), roded{at}tauex.tau.ac.il (R.S)
Competing Interest Statement
HB and EV own a limited number of stock options of Bionano Genomics Inc. HB is also employed part-time by Bionano Genomics Inc.
