Computational methods for analysing multiscale 3D genome organization

Zhang, Yang; Boninsegna, Lorenzo; Yang, Muyu; Misteli, Tom; Alber, Frank; Ma, Jian

doi:10.1038/s41576-023-00638-1

Cited by 23 publications

(4 citation statements)

References 221 publications

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“…Studies utilizing fluorescence in situ hybridization have delineated these territories, showcasing a radial pattern of genome organization [ 20 , 22 ]. The radial organization is rationalized by Hi-C analysis using graph theoretical techniques [ 21 , 52 ] and by polymer modeling of the Drosophila nucleus at resolution of individual topologically associating domains evolving throughout the interphase [ 19 ]. Eukaryotic nuclei, however, display a dynamic and active organization at all scales, throughout the interphase, senescence, diseases, and embryonic development [ 24 , 53 - 56 ].…”

Section: Discussionmentioning

confidence: 99%

Four-Dimensional Mesoscale Liquid Model of Nucleus Resolves Chromatin's Radial Organization

Laghmach,

Di Pierro,

Potoyan

2024

PRX Life

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Recent advances chromatin capture, imaging techniques, and polymer modeling have dramatically enhanced quantitative understanding of chromosomal folding. However, the dynamism inherent in genome architectures due to physical and biochemical forces and their impact on nuclear architecture and cellular functions remains elusive. While imaging of chromatin in four dimensions is becoming more common, there is a conspicuous lack of physics-based computational tools appropriate for revealing the forces that shape nuclear architecture and dynamics. To this end, we have developed a multiphase liquid model of the nucleus, which can resolve chromosomal territories, compartments, and nuclear lamina using a physics-based and data-informed free-energy function. The model enables rapid hypothesis-driven prototyping of nuclear dynamics in four dimensions, thereby facilitating comparison with whole nucleus imaging experiments. As an application, we model the Drosophila nucleus and map phase diagram of various possible nuclear morphologies. We shed light on the interplay of adhesive and cohesive interactions which give rise to distinct radial organization seen in conventional, inverted, and senescent nuclear architectures. The results also show the highly dynamic nature of the radial organization, the disruption of which leads to significant variability in domain coarsening dynamics and consequently variability of chromatin architecture. The model also highlights the impact of oblate nuclear geometry and heterochromatin-subtype interactions on the global chromatin architecture and local asymmetry of chromatin compartments.

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Section: Discussionmentioning

confidence: 99%

Four-Dimensional Mesoscale Liquid Model of Nucleus Resolves Chromatin's Radial Organization

Laghmach,

Di Pierro,

Potoyan

2024

PRX Life

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“…The mechanism and factors underlying enhancer-promoter (E-P) communication continue to be a subject of study, especially due to seemingly transient and dynamic nature of enhancers activation (Uyehara and Apostolou, 2023). Certainly, the advent of genetic engineering, single-cell methods, SRLCI approaches and 3D chromosome conformation capture-based technologies and their continuous improvement both on wet and in silico analysis, have pushed forward a deeper understanding of genome-wide mapping of E-P contacts, aiming at assigning one or multiple target genes to each enhancer, in time and space [for more details see (Brandão et al, 2021;Chen et al, 2023;Uyehara and Apostolou, 2023;Zhang et al, 2023)]. For example, intragenic enhancer at the PVT1 locus gene interacts strongly with the PVT1 promoter and weakly with the upstream MYC promoter gene.…”

Section: Principles Of 3d Genome Organization and Functionsmentioning

confidence: 99%

Enhancers dysfunction in the 3D genome of cancer cells

Della Chiara,

Jiménez,

Virdi

et al. 2023

Front. Cell Dev. Biol.

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Eukaryotic genomes are spatially organized inside the cell nucleus, forming a threedimensional (3D) architecture that allows for spatial separation of nuclear processes and for controlled expression of genes required for cell identity specification and tissue homeostasis. Hence, it is of no surprise that mis-regulation of genome architecture through rearrangements of the linear genome sequence or epigenetic perturbations are often linked to aberrant gene expression programs in tumor cells. Increasing research efforts have shed light into the causes and consequences of alterations of 3D genome organization. In this review, we summarize the current knowledge on how 3D genome architecture is dysregulated in cancer, with a focus on enhancer highjacking events and their contribution to tumorigenesis. Studying the functional effects of genome architecture perturbations on gene expression in cancer offers a unique opportunity for a deeper understanding of tumor biology and sets the basis for the discovery of novel therapeutic targets.

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“…(B) Cartoon of a topologically associated domain (TAD based on Hi-C) shows the folding of a contiguous chromatin fiber (modified with permission from Fig. 4 in 69 ). The access of individual components and large macromolecular complexes into the interior appears virtually unrestricted but may be constrained depending on the space-time dynamics of the fiber convolute ( C) Cartoon of an ~1 Mb chromatin domain (CD) based on 3D-SIM data shows a repressed core with densely compacted nucleosomes indicated as little grey dots (INC) and a decondensed periphery (ANC) with transcriptionally active loops expanding from the compact core (adapted from Fig.…”

Section: Introductionmentioning

confidence: 99%

Space-time dynamics of genome replication studied with super-resolved microscopy

Gelléri,

Sterr,

Strickfaden

et al. 2024

Preprint

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Genome replication requires duplication of the complete set of DNA sequences together with nucleosomes and epigenetic signatures. Notwithstanding profound knowledge on mechanistic details of DNA replication, major problems of genome replication have remained unresolved. In this perspective article, we consider the accessibility of replication machines to all DNA sequences in due course, the maintenance of functionally important positional and structural features of chromatid domains during replication, and the rapid transition of CTs into prophase chromosomes with two chromatids. We illustrate this problem with EdU pulse-labeling (10 min) and chase experiments (80 min) performed with mouse myeloblast cells. Following light optical serial sectioning of nuclei with 3D structured illumination microscopy (SIM), seven DNA intensity classes were distinguished as proxies for increasing DNA compaction. In nuclei of cells fixed immediately after the pulse-label, we observed a relative under-representation of EdU-labeled DNA in low DNA density classes, representing the active nuclear compartment (ANC), and an over-representation in high density classes representing the inactive nuclear compartment (INC). Cells fixed after the chase revealed an even more pronounced shift to high DNA intensity classes. This finding contrasts with previous studies of the transcriptional topography demonstrating an under-representation of epigenetic signatures for active chromatin and RNAPII in high DNA intensity classes and their over-representation in low density classes. We discuss these findings in the light of current models viewing CDs either as structural chromatin frameworks or as phase-separated droplets, as well as methodological limitations that currently prevent an integration of this contrasting evidence for the spatial nuclear topography of replication and transcription into a common framework of the dynamic nuclear architecture.

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Computational methods for analysing multiscale 3D genome organization

Cited by 23 publications

References 221 publications

Four-Dimensional Mesoscale Liquid Model of Nucleus Resolves Chromatin's Radial Organization

Four-Dimensional Mesoscale Liquid Model of Nucleus Resolves Chromatin's Radial Organization

Enhancers dysfunction in the 3D genome of cancer cells

Space-time dynamics of genome replication studied with super-resolved microscopy

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