Two-dimensional segmentation for analyzing Hi-C data

Lévy‐Leduc, Céline; Delattre, Maud; Mary‐Huard, Tristan; Robin, Stéphane

doi:10.1093/bioinformatics/btu443

Cited by 147 publications

(179 citation statements)

References 14 publications

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“…Hence, we performed genome-wide chromosome conformation capture (Hi-C) (Belton et al 2012) in HUVECs stimulated with TNF for 30 min, sequenced libraries to 200 million read pairs, obtained interaction maps (at 100-kbp resolution) (Supplemental Fig. S1C), computationally identified TAD boundaries (Lévy-Leduc et al 2014), and examined how TNF-responsive genes cluster within them. One thousand seventy-four genes upregulated at 30 min reside singly in a TAD, whereas 208 and 47 genes reside in a given TAD in pairs or groups of ≥3 genes, respectively; this also applies to down-regulated genes but with a notably higher number of 202 genes in groups of ≥3 per TAD.…”

Section: Tnf Stimulation Rapidly Remodels the Nascent Transcriptome Omentioning

confidence: 99%

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

et al. 2016

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Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells. NF-κB, the transcription factor complex driving the response, interferes with the regulatory machinery by binding active enhancers already in interaction with gene promoters. Notably, >50% of these enhancers do not encode canonical NF-κB binding motifs. Using a combination of genomics tools, we find that binding site selection plays a key role in NF-κΒ-mediated transcriptional activation and repression. We demonstrate the latter by describing the synergy between NF-κΒ and the corepressor JDP2. Finally, detailed analysis of a 2.8-Mbp locus using sub-kbp-resolution targeted chromatin conformation capture and genome editing uncovers how NF-κΒ that has just entered the nucleus exploits pre-existing chromatin looping to exert its multimodal role. This work highlights the involvement of topology in cis-regulatory element function during acute transcriptional responses, where primary DNA sequence and its higher-order structure constitute a regulatory context leading to either gene activation or repression.[Supplemental material is available for this article.]Mammalian cells, embedded in a multicellular environment, require intricate mechanisms in order to interpret, integrate, and ultimately respond to extracellular stimuli. Inflammatory signaling constitutes a well-studied example (Bhatt and Ghosh 2014; Smale and Natoli 2014); tumor necrosis factor (TNF) rapidly remodels gene expression programs through its main effector, nuclear factor κB (NF-κB) (Hayden and Ghosh 2008;Bhatt et al. 2012). TNF activates the same genes across cell types (Moynagh 2005), but the cascade needs to unfold against the ongoing transcriptional program of the stimulated cell. Along these lines, recent work in adipocytes showed that NF-κB is involved in gene repression via redistribution of prebound factors . This is tightly linked to the choice of NF-κB binding in vivo, but the specific principles that guide this choice in three-dimensional (3D) nuclear space and over time are still not well understood, despite the wealth of data on the different phases of the inflammatory response. For example, we now know that signaling directs binding of its downstream effectors to already-active cis-regulatory ele-

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Section: Tnf Stimulation Rapidly Remodels the Nascent Transcriptome Omentioning

confidence: 99%

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

et al. 2016

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“…A small number of algorithms that identify hierarchies of topological domains are available (Filippova et al 2014;Lévy-Leduc et al 2014;Shin et al 2015;Weinreb and Raphael 2015;Chen et al 2016;Shavit et al 2016). However, none of them provides a quantitative description of how the various layers of domains differ from one another.…”

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confidence: 99%

Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes

et al. 2017

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Understanding how regulatory sequences interact in the context of chromosomal architecture is a central challenge in biology. Chromosome conformation capture revealed that mammalian chromosomes possess a rich hierarchy of structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs) and sub-TAD contact domains. TADs appear to act as regulatory microenvironments by constraining and segregating regulatory interactions across discrete chromosomal regions. However, it is unclear whether other (or all) folding layers share similar properties, or rather TADs constitute a privileged folding scale with maximal impact on the organization of regulatory interactions. Here, we present a novel algorithm named CaTCH that identifies hierarchical trees of chromosomal domains in Hi-C maps, stratified through their reciprocal physical insulation, which is a single and biologically relevant parameter. By applying CaTCH to published Hi-C data sets, we show that previously reported folding layers appear at different insulation levels. We demonstrate that although no structurally privileged folding level exists, TADs emerge as a functionally privileged scale defined by maximal boundary enrichment in CTCF and maximal cell-type conservation. By measuring transcriptional output in embryonic stem cells and neural precursor cells, we show that the likelihood that genes in a domain are coregulated during differentiation is also maximized at the scale of TADs. Finally, we observe that regulatory sequences occur at genomic locations corresponding to optimized mutual interactions at the same scale. Our analysis suggests that the architectural functionality of TADs arises from the interplay between their ability to partition interactions and the specific genomic position of regulatory sequences.

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“…Variance was assumed to be constant for all kinds of contact intensities in Gaussian model. Domains were identified by maximizing the likelihood, and optimal solutions were found by dynamic programming [90].…”

Section: Hicsegmentioning

confidence: 99%

Developing bioimaging and quantitative methods to study 3D genome

et al. 2016

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The recent advances in chromosome configuration capture (3C)-based series molecular methods and optical superresolution (SR) techniques offer powerful tools to investigate three dimensional (3D) genomic structure in prokaryotic and eukaryotic cell nucleus. In this review, we focus on the progress during the last decade in this exciting field. Here we at first introduce briefly genome organization at chromosome, domain and sub-domain level, respectively; then we provide a short introduction to various super-resolution microscopy techniques which can be employed to detect genome 3D structure. We also reviewed the progress of quantitative and visualization tools to evaluate and visualize chromatin interactions in 3D genome derived from Hi-C data. We end up with the discussion that imaging methods and 3C-based molecular methods are not mutually exclusive ----actually they are complemental to each other and can be combined together to study 3D genome organization.Keywords: 3D Genome; quantitative methods; bioimaging; super resolution INTRODUCTIONIn eukaryotic nucleus, the organization of chromatin is very complex. Highly condensed chromatin and huge numbers of components, such as transcription factors, chromatin proteins and RNA-processing factors, cram together in a very small volume. Essential nuclear processes such as transcription, replication, and repair occur at spatially defined locations in the nucleus. Accumulating evidence suggests that the expression of many genes is correlated with their positions in cell nucleus, and the spatial organization of chromatins has played essential role in regulating transcriptional activity [1]. How these could be done is one of the greatest challenges in molecular biology. 1 DNA helix is hierarchically packaged into chromatin in an elegant way, and eventually form a chromosome in the eukaryotic nucleus over several levels of higher-order structures [1], indicating that a range of microscopy techniques with spatial and temporal scales that cover several orders of magnitude are necessary to understand the organization principles at different levels in a chromosome. For example, the structure of nucleosomes, the fundamental organization unit of chromatin, has been elucidated by X-ray crystals at nanometer scale [2]. The structure of "beads-on-a-string" fiber, which has a diameter of 11-nm and is the very first level of chromatin organization, is also well-understood through Electron Microscope [33]. However, substructure at the scale of 10-200 nm is poorly understood, especially in live cells, partly due to the requirement of biological system that the dynamics, process and function in biology need to be measured with high spatial (approximately nanometer) and temporal (approximately microsecond to millisecond) † These authors contributed equally to this work.

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Two-dimensional segmentation for analyzing Hi-C data

Cited by 147 publications

References 14 publications

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response

Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes

Developing bioimaging and quantitative methods to study 3D genome

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