Hierarchical chromatin organization detected by TADpole

Abstract

Mètodes computacionals; Genòmica

Métodos computacionales; Genómica

Computational Methods; Genomics

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.

European Research Council under the Seventh Framework Program FP7/2007-2013 [609989, in part]; European Union's Horizon 2020 Research and Innovation Programme [676556]; Spanish Ministry of Science and Innovation [BFU2013-47736-P, BFU2017-85926-P to M.A.M-R., IJCI-2015-23352 to I.F., BES-2014-070327 to P.S-V.]; ‘Centro de Excelencia Severo Ochoa 2013–2017’, SEV-2012-0208; CERCA Programme/Generalitat de Catalunya (to C.R.G.). Funding for open access charge: European Research Council under the Seventh Framework Program FP7/2007-2013 [609989]. We also acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the ‘Centro de Excelencia Severo Ochoa 2013-2017’, SEV-2012-0208, the CERCA Programme/Generalitat de Catalunya, Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, the Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and the Co-financing by the Spanish Ministry of Science and Innovation with funds from the European Regional Development Fund (ERDF) corresponding to the 2014-2020 Smart Growth Operating Program to the CRG.