The 4D nucleome project

Dekker, Job; Belmont, Andrew S.; Guttman, Mitchell; Leshyk, Victor O.; Lis, John T.; Lomvardas, Stavros; Mirny, Leonid A.; O’Shea, Clodagh C.; Park, Peter J.; Ren, Bing; Politz, Joan C. Ritland; Shendure, Jay; Zhong, Sheng

doi:10.1038/nature23884

Cited by 646 publications

(611 citation statements)

References 102 publications

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“…As shown in [21], the time average of 4D simulated datasets, even in the strong clustering regime, wipes out the sub-structure of snapshots when averaging over the entire G1 phase. An alternative approach has been to use polymer modeling to generate chromosome conformations, and to select those conformations that best match Hi-C data, so-called restraint-based polymer modeling [1]. Simultaneously, there have been efforts to develop methodologies to identify gene clusters in a rigorous and automated way from Hi-C data [26][27][28].…”

Section: Transient Crosslinking Timescale Influences Nucleolus Clustementioning

confidence: 99%

Transient crosslinking kinetics optimize gene cluster interactions

Walker

Taylor

Lawrimore

et al. 2019

Preprint

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Our understanding of how chromosomes structurally organize and dynamically interact has been revolutionized through the lens of long-chain polymer physics. Major protein contributors to chromosome structure and dynamics are condensin and cohesin that stochastically generate loops within and between chains, and entrap proximal strands of sister chromatids. In this paper, we explore the ability of transient, protein-mediated, gene-gene crosslinks to induce clusters of genes, thereby dynamic architecture, within the highly repeated ribosomal DNA that comprises the nucleolus of budding yeast. We implement three approaches: live cell microscopy; computational modeling of the full genome during G1 in budding yeast, exploring four decades of timescales for transient crosslinks between 5kbp domains (genes) in the nucleolus on Chromosome XII; and, temporal network models with automated community (cluster) detection algorithms applied to the full range of 4D modeling datasets. The data analysis tools detect and track gene clusters, their size, number, persistence time, and their plasticity (deformation). Of biological significance, our analysis reveals an optimal mean crosslink lifetime that promotes pairwise and cluster gene interactions through "flexible" clustering. In this state, large gene clusters self-assemble yet frequently interact (merge and separate), marked by gene exchanges between clusters, which in turn maximizes global gene interactions in the nucleolus. This regime stands between two limiting cases each with far less global gene interactions: with shorter crosslink lifetimes, "rigid" clustering emerges with clusters that interact infrequently; with longer crosslink lifetimes, there is a dissolution of clusters. These observations are compared with imaging experiments on a normal yeast strain and two condensin-modified mutant cell strains. We apply the same image analysis pipeline to the experimental and simulated datasets, providing support for the modeling predictions. Author SummaryThe spatiotemporal organization of the genome plays an important role in cellular processes involving DNA, but remains poorly understood, especially in the nucleolus, May 21, 2019 1/25 which does not facilitate conventional techniques. Polymer chain models have shown ability in recent years to make accurate predictions of the dynamics of the genome. We consider a polymer bead-chain model of the full yeast genome during the interphase portion of the cell cycle, featuring special dynamic crosslinking to model the effects of structural maintenance proteins in the nucleolus, and investigate how the kinetic timescale on which the crosslinks bind and unbind affects the resulting dynamics inside the nucleolus. It was previously known that when this timescale is sufficiently short, large, stable clusters appear, but when it is long, there is no resulting structure. We find that there additionally exists a range of timescales for which flexible clusters appear, in which beads frequently enter and leave clusters. Furthermore, we demonst...

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Section: Transient Crosslinking Timescale Influences Nucleolus Clustementioning

confidence: 99%

Transient crosslinking kinetics optimize gene cluster interactions

Walker

Taylor

Lawrimore

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…-F. Little clumps (Figure 2D),53 or lariat-like configurations(Figure 2E,F),23,54,55,[74][75][76] represent chromatin loops and domains as constituents of CTs. Hi-C, however, is not suitable to solve the problem of how these structuresare truly configured in space and time and also defies a solution of the problem of absolute compaction differences between euchromatic and heterochromatic structures and possible differences of how they can be accessed by TFs and other functionally relevant proteins.…”

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confidence: 99%

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

Cremer

2019

Genes Chromosomes & Cancer

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Transcription regulatory elements (TREs) have been extensively studied on the biochemical level with respect to their interactions with transcription factors (TFs), other DNA segments, and larger protein complexes. In this review, we describe concepts and preliminary experimental evidence for positional changes of TREs within a dynamic, functional nuclear architecture. We suggest a multilayered shell‐like chromatin organization of chromatin domain clusters with increasing chromatin compaction levels from the periphery toward the interior with a decondensed transcriptionally active peripheral layer and compact repressed chromatin typically located in the interior. This model organization of nuclear architecture implies a differential accessibility of TFs to targets located in co‐aligned active and inactive nuclear compartments (ANC and INC). It is based on evidence that active, easily accessible chromatin (perichromatin region, PR) lines a network of channels (interchromatin compartment, IC) involved in nuclear import–export functions. The IC and PR constitute the ANC, whereas transcriptionally noncompetent chromatin with higher compactness is part of the likely less accessible INC. Preliminary experimental evidence shows an enrichment of active TREs in the ANC and of inactive TREs in the INC suggesting positional changes of TREs between the ANC and INC depending on changes in their functional state.

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“…The three-dimensional (3D) context of the genome within the nucleus must also be considered when examining the outcome of infection. Recent advances in chromatin technologies have resulted in a leap from one-dimensional sequencing approaches to 3D chromosome capture [195,196]. In parallel, microscopy techniques have also developed allowing visualization down to individual nucleosomes [197].…”

Section: Discussionmentioning

confidence: 99%

Epigenetics and the dynamics of chromatin during adenovirus infections

et al. 2019

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Edited by Urs GreberAbbreviations ADP, adenovirus death protein; Ad5 or Ad 12, human adenovirus type 5 or 12, or other type referenced; BHK, baby hamster kidney; BrdU, bromodeoxyuridine; CTCF, CCCTC binding factor; DBS, double stranded break; DDR, DNA damage response; E1A, early 1 A; E4orf3 or E4orf6, early 4 open reading frame 3 or 6; HAdV-A12, human adenovirus subgroup A type 12, or different subgroup or type referenced; HMGB, high-mobility group box; hPaf1, human RNA polymerase II-associated factor 1; ISGs, interferon-stimulated genes; PML, promyelocytic leukemia; snRNP, small nuclear ribonuclear protein; SET or TAF-1, SE translocation or template activating factor; VRCs, viral replication centers.

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The 4D nucleome project

Cited by 646 publications

References 102 publications

Transient crosslinking kinetics optimize gene cluster interactions

Transient crosslinking kinetics optimize gene cluster interactions

Nuclear compartmentalization, dynamics, and function of regulatory DNA sequences

Epigenetics and the dynamics of chromatin during adenovirus infections

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