Chromatin network rearrangements in differentiation and cancer reveal connections between evolutionary processes and gene regulation DOI Creative Commons
Flavien Raynal,

Kaustav Sengupta,

Dariusz Plewczyński

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Nov. 2, 2023

Cancer cells are highly plastic, allowing them to adapt changing conditions. Genes related basic cellular processes evolved in ancient species, while more specialized genes appeared later with multicellularity (metazoan genes) or even after mammals evolved. Transcriptomic analyses have shown that up-regulated cancer, metazoan-origin inactivated. Despite the importance of these observations, underlying mechanisms remain unexplored. Here, we study local and global epigenomic may regulate from specific evolutionary periods. Using gene age data, characterize landscape, expression regulation, chromatin organization three cell types: human embryonic stem cells, normal B-cells, primary Chronic Lymphocytic Leukemia, a B-cell malignancy. We identify topological changes during differentiation observing patterns Polycomb repression RNA Polymerase II pausing, which reversed oncogenesis. Beyond non-random features 3D epigenome, suggest lead preferential interactions among ancient, intermediate, recent genes, mediated by II, Polycomb, lamina, respectively. Our findings shed light on regulation according this across

Language: Английский

Loop stacking organizes genome folding from TADs to chromosomes DOI
Antonina Hafner, Minhee Park, Scott E. Berger

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(9), P. 1377 - 1392.e6

Published: May 1, 2023

Language: Английский

Citations

72
Design principles of 3D epigenetic memory systems DOI
Jeremy A. Owen, Dino Osmanović, Leonid A. Mirny

et al.

Science, Journal Year: 2023, Volume and Issue: 382(6672)

Published: Nov. 16, 2023

Cells remember their identities, in part, by using epigenetic marks-chemical modifications placed along the genome. How can mark patterns remain stable over cell generations despite constant erosion replication and other processes? We developed a theoretical model that reveals three-dimensional (3D) genome organization stabilize memory as long (i) there is large density difference between chromatin compartments, (ii) modifying "reader-writer" enzymes spread marks three dimensions, (iii) are limited abundance relative to histone substrates. Analogous an associative encodes neuronal connectivity, encoded 3D network of chromosomal contacts. Our provides unified account diverse observations key role memory.

Language: Английский

Citations

48
Dynamic PRC1–CBX8 stabilizes a porous structure of chromatin condensates DOI Creative Commons
Michael Uckelmann, Vita Levina, Cyntia Taveneau

et al.

Nature Structural & Molecular Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 15, 2025

The compaction of chromatin is a prevalent paradigm in gene repression. Chromatin commonly thought to repress transcription by restricting accessibility. However, the spatial organization and dynamics compacted gene-repressing factors are unknown. Here, using cryo-electron tomography, we solved three-dimensional structure condensed polycomb repressive complex 1 (PRC1) with CBX8. PRC1-condensed porous stabilized through multivalent dynamic interactions PRC1 chromatin. Mechanistically, positively charged residues on internally disordered regions CBX8 mask negative charges DNA stabilize state Within condensates, remains while maintaining static structure. In differentiated mouse embryonic stem cells, CBX8-bound accessible. These findings challenge idea rigidly domains instead provide mechanistic framework for accessible PRC1–chromatin condensates. Here authors show that gene-inactivating protein packs inactive genes into study challenges traditional views restricted accessibility low cause

Language: Английский

Citations

4
Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance DOI
Rakesh Kumar Sahu,

Jothy Dhakshnamoorthy,

Shweta Jain

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(17), P. 3175 - 3191.e8

Published: Aug. 2, 2024

Language: Английский

Citations

11
Principles of long-range gene regulation DOI Creative Commons
Sanyami Zunjarrao, Maria Cristina Gambetta

Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 91, P. 102323 - 102323

Published: Feb. 13, 2025

Transcription from gene promoters occurs in specific spatiotemporal patterns multicellular organisms, controlled by genomic regulatory elements. The communication between a element and promoter requires certain degree of physical proximity them; hence, most regulation locally the genome. However, recent discoveries have revealed long-range strategies that enhance interactions elements overcoming distances them linear These new findings challenge traditional view how expression are controlled. This review examines recently reported Drosophila mammals, offering insights into their mechanisms evolution.

Language: Английский

Citations

2
Chromatin compaction by Polycomb group proteins revisited DOI Creative Commons
Michael Uckelmann, Chen Davidovich

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 86, P. 102806 - 102806

Published: March 27, 2024

The chromatin compaction activity of Polycomb group proteins has traditionally been considered essential for transcriptional repression. However, there is very little information on how compact at the molecular level and no causal link between compactness Recently, a more complete picture Polycomb-dependent architecture started to emerge, owing advanced methods imaging chromosome conformation capture. Discoveries into Polycomb-driven phase separation add another layer complexity. Recent observations generally imply that modulate structure multiple scales reduce its dynamics segregate it from active domains. Hence, reasonable hypothesise maintain energetically favourable state compacted chromatin, rather than actively it.

Language: Английский

Citations

9
Phase separation and inheritance of repressive chromatin domains DOI Creative Commons

Nazli Akilli,

Thierry Cheutin, Giacomo Cavalli

et al.

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 86, P. 102201 - 102201

Published: May 2, 2024

Polycomb-associated chromatin and pericentromeric heterochromatin form genomic domains important for the epigenetic regulation of gene expression. Both Polycomb complexes factors rely on 'read write' mechanisms, which, their own, are not sufficient to explain formation maintenance these domains. Microscopy has revealed that they specific nuclear compartments separated from rest genome. Recently, some subunits molecular machineries have been shown undergo phase separation, both in vitro vivo, suggesting separation might play roles function two kinds repressive chromatin. In this review, we will present recent advances field facultative constitutive through separation.

Language: Английский

Citations

6
Navigating the complexity of Polycomb repression: Enzymatic cores and regulatory modules DOI
Simone Tamburri, Samantha Rustichelli,

Simona Amato

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(18), P. 3381 - 3405

Published: Aug. 23, 2024

Language: Английский

Citations

6
Enhancer‐dependent gene regulation in space, time, and malignancies DOI Creative Commons

Beat Blum,

Victoria Dachtler,

Angelika Feldmann

et al.

International Journal of Cancer, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Control of cell-type-specific gene activation requires the coordinated activity distal regulatory elements, including enhancers, whose inputs must be temporally integrated. Dysregulation this capacity, such as aberrant usage can result in malignant transformation cells. In review, we provide an overview our current understanding enhancer-driven regulation and discuss how may integrated across time, followed by epigenetic structural alterations enhancers cancers.

Language: Английский

Citations

0
Microscopy methods for the in vivo study of nanoscale nuclear organization DOI Creative Commons

Nidhi Rani Lokesh,

Mark E. Pownall

Biochemical Society Transactions, Journal Year: 2025, Volume and Issue: 53(01)

Published: Feb. 3, 2025

Eukaryotic genomes are highly compacted within the nucleus and organized into complex 3D structures across various genomic physical scales. Organization plays a key role in gene regulation, both facilitating regulatory interactions to promote transcription while also enabling silencing of other genes. Despite functional importance genome organization determining cell identity function, investigating nuclear this wide range scales has been challenging. Microscopy provides opportunity for direct visualization pioneered discoveries field. Nonetheless, nanoscale nucleus, such as nucleosomes chromatin loops, requires super-resolution imaging go beyond ~220 nm diffraction limit. Here, we review recent advances technology their promise uncover new insights at nanoscale. We discuss different modalities how they have applied with focus on light microscopy its application vivo systems. Finally, conclude our perspective continued technical innovations will advance understanding structure function.

Language: Английский

Citations

0