On the existence and functionality of topologically associating domains

Beagan, Jonathan A.; Phillips-Cremins, Jennifer E.

doi:10.1038/s41588-019-0561-1

Cited by 273 publications

(270 citation statements)

References 69 publications

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“…Whether TADs regulate transcription and/or are a consequence of transcription is currently under intense debate [35][36][37] . Here, we present evidence that a nucleosome-contrained LEF model can predict TADs based solely on the organization of transcriptional units, implying that transcription can be a major determinant of local chromatin organization.…”

Section: Single-molecule Experiments Show That Nucleosomes Impede Cohmentioning

confidence: 99%

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Bailey

Surovtsev

Williams

et al. 2020

Preprint

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Chromosome conformation capture techniques (e.g Hi-C) reveal that intermediate-scale chromatin organization is comprised of “topologically associating domains” (TADs) on the tens to thousands of kb scale.1–5 The loop extrusion factor (LEF) model6–10 provides a framework for how TADs arise: cohesin or condensin extrude DNA loops, until they encounter boundary elements. Despite recent in vitro studies demonstrating that cohesin and condensin can drive loop formation on (largely) naked DNA11–13, evidence supporting the LEF model in living cells is lacking. Here, we combine experimental measurements of chromatin dynamics in vivo with simulations to further develop the LEF model. We show that the activity of the INO80 nucleosome remodeler enhances chromatin mobility, while cohesin and condensin restrain chromatin mobility. Motivated by these findings and the observations that cohesin is loaded preferentially at nucleosome-depleted transcriptional start sites14–18 and its efficient translocation requires nucleosome remodeling19–23 we propose a new LEF model in which LEF loading and loop extrusion direction depend on the underlying architecture of transcriptional units. Using solely genome annotation without imposing boundary elements, the model predicts TADs that reproduce experimental Hi-C data, including boundaries that are CTCF-poor. Furthermore, polymer simulations based on the model show that LEF-catalyzed loops reduce chromatin mobility, consistent with our experimental measurements. Overall, this work reveals new tenets for the origins of TADs in eukaryotes, driven by transcription-coupled nucleosome remodeling.

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Section: Single-molecule Experiments Show That Nucleosomes Impede Cohmentioning

confidence: 99%

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Bailey

Surovtsev

Williams

et al. 2020

Preprint

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“…There is also evidence for spatial arrangement within the cell nuclei (Thévenin, Ein-Dor, Ozery-Flato, & Shamir, 2014), and genomic regions that are found to be in contact with each other are known as Topologically Associated Domains (TADs). The implication for these regions are currently being investigated see (Beagan & Phillips-Cremins, 2020) for a review. Another question is whether genes can perform different functions in different tissues depending on the availability of other genes in the network (McCole, Erceg, Saylor, & Wu, 2018).…”

Section: Domestication and The Domestication Syndromementioning

confidence: 99%

Genomics and Transcriptomics of Behaviour and Plumage Colouration

Fogelholm

2020

Linköping Studies in Science and Technology. Dissertations

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The aim throughout this thesis has been to investigate the underlying genetics of behaviours and feather colour and plumage patterns by using chickens as a model organism. Chickens are extremely important as a food source, both in terms of egg, as well as meat production. As such there is a large research interest for them, and they provide an excellent model to study the effects of domestication and evolution, since the ancestor to our domestic breeds the Red Junglefowl can still be found living freely in the wild. This allows us to set up long term crossing experiments where we can harness the power of recombination events and genome wide sequencing to perform genome wide mapping studies. I also want to take the opportunity to integrate the results from all of my work and consider it in perspective of the domestication syndrome. In Paper I we investigated the Social Reinstatement behaviour which combines aspects of sociality and anxiousness. We detected several QTL and some overlap with Open Field behaviour from previous work within the group. By combining genomic and transcriptomic methods three strong candidate genes were found: TTRAP, ACOT9 and PRDX4.

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“…Compartments are distinct from topologically associating domains (TADs), another structure found with high-resolution Hi-C. TADs are defined by their high concentration of contacts 2 within their domain, relative to their low level of interaction across different TADs (8)(9)(10)(11). Intra-TAD contacts vary from cell to cell (3,(12)(13)(14), but most TAD boundaries are conserved across single cells (3), cell types (7,9,11,15) and species (9,15,16). In addition to TADs, that range from a few kilo bases to around 1 million bases long (8)(9)(10)(11), smaller TAD-like structures, called sub-TADs have been discovered within TADs (4,(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

“…Finally, at the highest resolution, chromatin loops can be observed. They represent contacts between DNA regions, including promoters and enhancers (7,13,(17)(18)(19), usually stabilized by CTCF or other structural proteins (15,16,20).…”

Section: Introductionmentioning

confidence: 99%

“…Co-regulation might thus be driven by sub-TAD structures such as cis-regulatory domains (27), insulation neighbourhoods (28) or co-expression domains (CODs) (26). Those seemingly contradictory observations show the shortcomings of our understanding of transcription with respect to chromatin architecture (8,13). CODs are especially interesting to us as they are purely defined from a transcriptional point of view.…”

Section: Introductionmentioning

confidence: 99%

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Genes on Different Strands Mark Boundaries Associated with Co-regulation Domains

Baguette

Bilodeau

Bourque

2020

Preprint

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Gene regulation is influenced by chromatin conformation. Current models suggest that topologically associating domains (TADs) act as regulatory units, which could also include distinct co-expression domains (CODs) favouring correlated gene expression. We integrated publicly available RNA-seq, ChIP-seq and Hi-C data from A549 cells stimulated with the glucocorticoid dexamethasone to explore how differentially expressed genes are co-regulated among TADs and CODs. Interestingly, we found that gene position and orientation also impact co-regulation. Indeed, divergent and convergent pairs of genes we enriched at sub-TAD boundaries, forming distinct CODs. We also found that genes at COD boundaries were less likely to be separated by structural proteins such as Cohesin and CTCF. A complementary analysis of lung expression quantitative trait loci (eQTL) demonstrated that genes affected by the same variant were more likely to be found on the same strand while lacking a TAD boundary. Taken together, these results suggest a model where gene orientation can provide a boundary between CODs, at the sub-TAD level, thus affecting their likelihood of co-regulation.

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On the existence and functionality of topologically associating domains

Cited by 273 publications

References 69 publications

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Loops and the activity of loop extrusion factors constrain chromatin dynamics

Genomics and Transcriptomics of Behaviour and Plumage Colouration

Genes on Different Strands Mark Boundaries Associated with Co-regulation Domains

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