Retrieving high-resolution chromatin interactionsand decoding enhancer regulatory potential in silico

Abstract

The advent of the chromosome conformation capture (3C) and related technologies has profoundly renewed our understaning of three-dimensional chromatin organization in mammalian nuclei. Alongside these experimental approaches, numerous computational tools for handling, normalizing, visualizing, and ultimately detecting interactions in 3C-type datasets are being developed. Here, we present Bloom, a comprehensive method for the analysis of 3C-type data matrices on the basis of Dirichlet process mixture models that addresses two important open issues. First, it retrieves occult interaction patterns from sparse data, like those derived from single-cell Hi-C experiments; thus, bloomed sparse data can now be used to study interaction landscapes at sub-kbp resolution. Second, it detects enhancer-promoter interactions with high sensitivity and inherently assigns an interaction frequency score (IFS) to each contact. Using enhancer perturbation data of different throughput, we show that IFS accurately quantifies the regulatory influence of each enhancer on its target promoter. As a result, Bloom allows decoding of complex regulatory landscapes by generating functionally-relevant enhancer atlases solely on the basis of 3C-type of data.