Deciphering hierarchical organization of topologically associated domains through change-point testing

TL;DR

This paper introduces HiCKey, a new method for detecting hierarchical TAD structures in Hi-C data, revealing multi-layered chromatin organization and its relation to gene regulation.

Contribution

HiCKey employs a generalized likelihood-ratio test and optimal search strategies to accurately identify hierarchical TADs and compare them across samples, advancing chromatin structure analysis.

Findings

Most TADs have no more than four hierarchical layers.

Active chromosomal regions show more complex TAD hierarchies.

HiCKey demonstrates high precision and robustness in TAD detection.

Abstract

Background: The nucleus of eukaryotic cells spatially packages chromosomes into a hierarchical and distinct segregation that plays critical roles in maintaining transcription regulation. High-throughput methods of chromosome conformation capture, such as Hi-C, have revealed topologically associating domains (TADs) that are defined by biased chromatin interactions within them. Results: Here, we introduce a novel method, HiCKey, to decipher hierarchical TAD structures in Hi-C data and compare them across samples. We first derive a generalized likelihood-ratio (GLR) test for detecting change-points in an interaction matrix that follows a negative binomial distribution or general mixture distribution. We then employ several optimal search strategies to decipher hierarchical TADs with p-values calculated by the GLR test. Large-scale validations of simulation data show that HiCKey has good precision in recalling known TADs and is robust against random collision noise of chromatin interactions. By applying HiCKey to Hi-C data of seven human cell lines, we identified multiple layers of TAD organization among them, but the vast majority had no more than four layers. In particular, we found that TAD boundaries are significantly enriched in active chromosomal regions compared to repressed regions, indicating finer hierarchical architectures in active regions for precise gene transcription regulation. Conclusions: HiCKey is optimized for processing large matrices constructed from high-resolution Hi-C experiments. The method and theoretical result of the GLR test provide a general framework for significance testing of similar experimental chromatin interaction data that may not fully follow negative binomial distributions but rather more general mixture distributions.