Author response: Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells

Freire-Pritchett, Paula; Schoenfelder, Stefan; Várnai, Csilla; Wingett, Steven; Cairns, Jonathan; Collier, Amanda J.; García-Vílchez, Raquel; Furlan-Magaril, Mayra; Osborne, Cameron S.; Fraser, Peter; Rugg‐Gunn, Peter J.; Spivakov, Mikhail

doi:10.7554/elife.21926.032

Cited by 3 publications

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“…To obtain a global overview of the chromatin interactions that take place between gene promoters and other genomic regions, across cell types and species, we collected and processed publicly available Promoter Capture Hi-C (PCHi-C) data for human (Choy et al, 2018;Freire-Pritchett et al, 2017;Javierre et al, 2016;Mifsud et al, 2015;Pan et al, 2018;Rubin et al, 2017) and mouse samples (Comoglio et al, 2018;Koohy et al, 2018;Novo et al, 2018;Schoenfelder et al, , 2018Siersbaek et al, 2017). To ensure data comparability, we selected PCHi-C datasets that were generated with experimental procedures similar to those described by Schoenfelder and co-authors .…”

Section: Promoter Capture Hic Data Processingmentioning

confidence: 99%

“…CC-BY-NC 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 26, 2021. ; https://doi.org/10.1101/2021.02.26.432473 doi: bioRxiv preprint perform a comparative analysis of cis-regulatory landscapes, based on high-resolution promoter-centered chromatin interaction maps for human and mouse (Choy et al, 2018;Comoglio et al, 2018;Freire-Pritchett et al, 2017;Javierre et al, 2016;Koohy et al, 2018;Mifsud et al, 2015;Novo et al, 2018;Pan et al, 2018;Rubin et al, 2017;Siersbaek et al, 2017). By contrasting this data with simulated regulatory landscapes, we show that there is significant evolutionary conservation of promoterenhancer chromatin contact maps, even at large genomic distances, suggesting that genomic rearrangements that perturb regulatory interactions are counter-selected.…”

Section: Introductionmentioning

confidence: 99%

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Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

Laverré

Tannier

Necşulea

2021

Preprint

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Gene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements is rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve regulatory element sequences and their interactions with target genes. The extent of evolutionary conservation is remarkable for long-range promoter-enhancer contacts, illustrating how the structure of regulatory interactions constrains large-scale genome evolution. Notably, we show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny or contacts with target genes, is tightly linked to gene expression evolution. Keywords : cis-regulatory landscapes, gene expression evolution, large-scale genome evolution, Promoter Capture Hi-C

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Section: Promoter Capture Hic Data Processingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

Laverré

Tannier

Necşulea

2021

Preprint

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Network analysis of promoter interactions reveals the hierarchical differences in genome organisation between human pluripotent states

Chovanec

Collier

Krueger

et al. 2019

Preprint

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SUMMARYA complex and poorly understood interplay between 3D genome organisation, transcription factors and chromatin state underpins cell identity. To gain a systems-level understanding of this interplay, we generated a high-resolution atlas of annotated chromatin interactions in naïve and primed human pluripotent stem cells and developed a network-graph approach to examine the atlas at multiple spatial scales. Investigating chromatin interactions as a network uncovered highly connected hubs that changed substantially in interaction frequency and in transcriptional co-regulation between pluripotent states.Small hubs frequently merged to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. Importantly, we identified state-specific differences in enhancer activity and interactivity that corresponded with widespread reconfiguration of transcription factor binding and target gene expression. These findings provide multilayered insights into the gene regulatory control of human pluripotency and our systems-based network approach could be applied broadly to uncover new principles of 3D genome organisation. RESULTS Promoter interaction mapping in naïve and primed human PSCsWe used PCHi-C to profile the global, high-resolution interactomes of 22,101 promoters in isogenic human naïve and primed PSCs. There was a strong concordance in pairwise interaction read counts between the biological replicates of the same cell type (r 2 >0.95; Figure S1A); therefore we merged replicates for all downstream analyses. PCHi-C data normalisation and signal detection using the CHiCAGO pipeline (Cairns et al., 2016) identified 75,091 significant cis-interactions between baited promoters and other genomic regions in naïve PSCs, and 83,782 in primed PSCs ( Figure S1B). Just under half of the interactions were common to both cell types (n=39,360). As expected, trans-interactions represented a small minority of promoter interactions (354 interactions). In both cell types, the majority of significant interactions were between the promoters of protein-coding genes and non-promoter genomic regions ( Figure S1B).Processed datasets from this large-scale resource are available through the Open Science Framework (https://osf.io/XXXXX) and Table S1, and raw sequencing reads have been deposited to the Gene Expression Omnibus (accession GSEXXXXXX). Network visualisation of promoter interactomesWe next developed a computational approach called Canvas (Chromosome architecture network visualisation at scales) to visualise high-resolution, capture-based DNA interaction data at a network scale.Network graphs were constructed where each node of the network represents an individual HindIII genomic fragment (average size, 4 kb) and each edge represents a significant interaction between nodes ( Figure 1A). We combined all significant interactions detected in naïve and primed PSCs to produce a single, unified network graph, which retains information about whether an interaction is shared or cell type-specific ( Figu...

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Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

Thiecke

Wutz

Muhar

et al. 2020

Preprint

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It is currently assumed that 3D chromosomal organisation plays a central role in transcriptional control. However, recent evidence shows that steady-state transcription of only a minority of genes is affected by depletion of architectural proteins such as cohesin and CTCF. Here, we have used Capture Hi-C to interrogate the dynamics of chromosomal contacts of all human gene promoters upon rapid architectural protein degradation. We show that promoter contacts lost in these conditions tend to be long-range, with at least one interaction partner localising in the vicinity of topologically associated domain (TAD) boundaries. In contrast, many shorter-range chromosomal contacts, particularly those that connect active promoters with each other and with active enhancers remain unaffected by cohesin and CTCF depletion. We demonstrate that the effects of cohesin depletion on nascent transcription can be explained by changes in the connectivity of their enhancers. Jointly, these results provide a mechanistic explanation to the limited, but consistent effects of cohesin and CTCF on steady-state transcription and point towards the existence of alternative enhancer-promoter pairing mechanisms that are independent of these proteins.

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Author response: Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells

Cited by 3 publications

References 0 publications

Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

Long-range promoter-enhancer contacts are conserved during evolution and contribute to gene expression robustness

Network analysis of promoter interactions reveals the hierarchical differences in genome organisation between human pluripotent states

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

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