TADCompare: An R Package for Differential and Temporal Analysis of Topologically Associated Domains

Cresswell, Kellen Garrison; Dozmorov, Mikhail G.

doi:10.3389/fgene.2020.00158

Cited by 49 publications

(52 citation statements)

References 103 publications

(172 reference statements)

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“…4 g). The boundary consolidation score appears to provide a robust metric of boundary strength, since both the insulation [ 42 ] and boundary score [ 43 ] metrics increase linearly as a function of boundary identity (Additional file 1 : Fig. S6).…”

Section: Resultsmentioning

confidence: 99%

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Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries

2020

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Background Topologically associating domains (TADs) are genomic regions of self-interaction. Additionally, it is known that TAD boundaries are enriched in CTCF binding sites. In turn, CTCF sites are known to be asymmetric, whereby the convergent configuration of a pair of CTCF sites leads to the formation of a chromatin loop in vivo. However, to date, it has been unclear how to reconcile TAD structure with CTCF-based chromatin loops. Results We approach this problem by analysing CTCF binding site strengths and classifying clusters of CTCF sites along the genome on the basis of their relative orientation. Analysis of CTCF site orientation classes as a function of their spatial distribution along the human genome reveals that convergent CTCF site clusters are depleted while divergent CTCF clusters are enriched in the 5- to 100-kb range. We then analyse the distribution of CTCF binding sites as a function of TAD boundary conservation across seven primary human blood cell types. This reveals divergent CTCF site enrichment at TAD boundaries. Furthermore, convergent arrays of CTCF sites separate the left and right sections of TADs that harbour internal CTCF sites, resulting in unequal TAD ‘halves’. Conclusions The orientation-based CTCF binding site cluster classification that we present reconciles TAD boundaries and CTCF site clusters in a mechanistically elegant fashion. This model suggests that the emergent structure of nuclear chromatin in the form of TADs relies on the obligate alternation of divergent and convergent CTCF site clusters that occur at different length scales along the genome. Graphical abstract

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Section: Resultsmentioning

confidence: 99%

“…4 g), the insultation score [ 42 ] (Additional file 1 : Fig. S6B) and the boundary score calculated by the TADCompare package [ 43 ] (Additional file 1 : Fig. S6C).…”

Section: Methodsmentioning

confidence: 99%

Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries

2020

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“…Changes in TAD boundaries, as found in cancer, can induce major changes in gene expression 15 . We compared TADs between basal and stimulated FLS with TADCompare 16 . TADCompare classifies TADs as either non-differential or differential based on changes in position or strength of TAD boundaries.…”

Section: Resultsmentioning

confidence: 99%

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Frank-Bertoncelj

Klein

et al. 2020

Preprint

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Genome-wide association studies have reported >100 risk loci for rheumatoid arthritis (RA). These loci have been shown to be enriched in immune cell-specific enhancers, but analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrated DNA architecture (ChIP-seq), 3D chromatin interactions (HiC, capture HiC), DNA accessibility (ATAC-seq) and gene expression (RNA-seq) in FLS, B cells and T cells with genetic fine mapping of RA loci. We identified putative causal variants, enhancers, genes, and cell types for 30 - 60% of RA loci and demonstrated that FLS account for up to 24% of RA heritability. TNF stimulation of FLS altered the organization of topologically associating domains (TADs), chromatin state and the expression of putative causal genes (e.g. TNFAIP3, IFNAR1). Several putative causal genes constituted RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrated that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.

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“…As previously defined 62 , the TAD boundary regions were defined as the flanking 100kb region of the boundary bins, and the region between these TAD boundary regions was considered as being inside the TADs. Matched TADs: if both boundaries of a TAD in one condition aligned within TAD boundary regions in another condition.…”

Section: Methodsmentioning

confidence: 99%

DeTOKI identifies and characterizes the dynamics of chromatin topologically associating domains in a single cell

Zhang

2021

Preprint

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The human genome has a dynamic, well-organized hierarchical 3D architecture, including megabase-sized topologically associating domains (TAD). TADs are a key structure of the genome regulating nuclear processes, such as gene expression, DNA replication and damage repair. However, owing to a lack of proper computational tools, TADs have still not been systematically and reliably surveyed in single cells. In the present work, we developed a new algorithm to decode TAD boundaries that keep chromatin interaction insulated (deTOKI) from ultra-sparse Hi-C data. By nonnegative matrix factorization, this novel algorithm seeks out for regions that insulate the genome into blocks with minimal chance of clustering. We found that deTOKI outperformed competing tools and that it reliably identified TADs with single-cell Hi-C (scHi-C) data. By applying deTOKI, we found that domain structures are prevalent in single cells. Further, although domain structures are highly dynamic between cells, TADs adhere to the ensemble, suggesting tight regulation of single-cell TADs. Finally, we found that the insulation properties of TAD boundaries have major effect on the epigenetic landscape in individual cells. In sum, deTOKI serves as a powerful tool for profiling TADs in single cells.

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TADCompare: An R Package for Differential and Temporal Analysis of Topologically Associated Domains

Cited by 49 publications

References 103 publications

Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries

Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

DeTOKI identifies and characterizes the dynamics of chromatin topologically associating domains in a single cell

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