Hierarchical chromatin organization detected by TADpole

Abstract

The rapid development of Chromosome Conformation Capture (3C-based techniques), as well as imaging together with bioinformatics analyses, has been fundamental for unveiling that chromosomes are organized into the so-called topologically associating domains or TADs. While TADs appear as nested patterns in the 3C-based interaction matrices, the vast majority of available TAD callers are based on the hypothesis that TADs are individual and unrelated chromatin structures. Here we introduce TADpole, a computational tool designed to identify and analyze the entire hierarchy of TADs in intra-chromosomal interaction matrices. TADpole combines principal component analysis and constrained hierarchical clustering to provide a set of significant hierarchical chromatin levels in a genomic region of interest. TADpole is robust to data resolution, normalization strategy and sequencing depth. Domain borders defined by TADpole are enriched in main architectural proteins (CTCF and cohesin complex subunits) and in the histone mark H3K4me3, while their domain bodies, depending on their activation-state, are enriched in either H3K36me3 or H3K27me3, highlighting that TADpole is able to distinguish functional TAD units. Additionally, we demonstrate that TADpole's hierarchical annotation, together with the new DiffT score, allows for detecting significant topological differences on Capture Hi-C maps between wild-type and genetically engineered mouse.

Pre-configuring chromatin architecture with histone modifications guides hematopoietic stem cell formation in mouse embryos

“…1d). It was in accordance with the past observation that most TAD boundary regions displayed H3K4me3 enrichments [38][39][40][41] . Using top 1000 variable TAD boundaries on four populations, we identified four main clusters with increased or decreased boundary strengths (Fig.…”

Systematic inference and comparison of multi-scale chromatin sub-compartments connects spatial organization to cell phenotypes

“…Importantly, the position of a compartment domain in the dendrogram can vary across cell models since it depends exclusively on 3D-proximity with other domains. This is in stark contrast to previous approaches inferring TAD hierarchies 19 – 21 , which invariably preserved TAD 1D-proximity, i.e., two contiguous TADs along the genome sequence will also be contiguous in the inferred hierarchy. We called our approach Calder to draw a suggestive analogy between the nonstatic nature of compartment domain hierarchies and the mobile sculptures of Alexander Calder (Supplementary Fig.…”

A comparison of topologically associating domain callers over mammals at high resolution

“…Soler-Vila et al [ 83 ] developed a clustering method based on combining principal component analysis and constrained hierarchical clustering, called TADpole. TADpole has three main steps: 1- Preprocessing of the input interaction matrix by principal component analysis, 2- Constrained hierarchical clustering optimization, and 3- Genome segmentation.…”