OnTAD: hierarchical domain structure reveals the divergence of activity among TADs and boundaries

Abstract

The spatial organization of chromatin in the nucleus has been implicated in regulating gene expression. Maps of high-frequency interactions between different segments of chromatin have revealed topologically associating domains (TADs), within which most of the regulatory interactions are thought to occur. TADs are not homogeneous structural units but appear to be organized into a hierarchy. We present OnTAD, an optimized nested TAD caller from Hi-C data, to identify hierarchical TADs. OnTAD reveals new biological insights into the role of different TAD levels, boundary usage in gene regulation, the loop extrusion model, and compartmental domains. OnTAD is available at https://github.com/anlin00007/OnTAD.

An integrative view of the regulatory and transcriptional landscapes in mouse hematopoiesis

“…The target gene assignments can be refined by inclusion of data on chromatin interaction frequencies, for example, by restricting cCRE-gene pairs to those within a TAD (Oudelaar et al 2017). The VISION project has analyzed Hi-C data in G1E-ER4 cells (Hsu et al 2017) and HPC7 cells (Wilson et al 2016) to provide coordinates of TADs (An et al 2019) and compartments (Zheng and Zheng 2018), and our query interface allows users to use this information to refine choices of cCREs for specific genes.…”

“…(D) Illustration of eRP scores for cCREs in and around the Alas2 gene, including a comparison with previously measured enhancer and promoter activities. Nested TADs called by OnTAD (An et al 2019) are shown in the bottom tracks.…”

Topologically associating domain (TAD) boundaries stable across diverse cell types are evolutionarily constrained and enriched for heritability

“…Although the heritability enrichment patterns are similar across cell types and TADs have been characterized as largely invariant across cell types [19,20,35–37], previous work suggests distinct functional properties among TAD boundaries with different insulatory strengths, hierarchical structures, and cell types of activity [32,41,42]. Thus, we hypothesized that the stability of TAD boundaries across cell types would be informative about their functional importance and conservation.…”

“…For example, stratifying boundaries by their strength (in a single cell type) facilitated discovery that greater CTCF binding confers stronger insulation and that super-enhancers are preferentially insulated by the strongest boundaries [41]. Stratifying by hierarchical properties of TADs—TADs often have sub-TADs—demonstrated that boundaries flanking higher-level structures are enriched for CTCF, active epigenetic states, and higher gene expression [42].…”

Detecting local changes in chromatin architecture with false discovery control

“…However, these results are often irreproducible due to their susceptibility to high stochasticity inherent to Hi-C data 16 . Another approach involves calling TADs in two conditions, then comparing the called boundaries 13,17,18,19,20 . However, TAD callers identify boundaries inconsistently even within replicate experiments 21,22 , raising questions about the suitability of this approach for reliably identifying differences between experimental conditions.…”