Heterochromatin Networks: Topology, Dynamics, and Function (a Working Hypothesis)

Ērenpreisa, Jekaterina; Krigerts, Jekabs; Salmiņa, Kristīne; Gerashchenko, Bogdan I.; Freivalds, Tālivaldis; Kurg, Reet; Winter, Ruth; Krufczik, Matthias; Zayakin, Pawel; Hausmann, Michael; Giuliani, Alessandro

doi:10.3390/cells10071582

Cited by 15 publications

(22 citation statements)

References 142 publications

(182 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The generation of polyploid giant nuclei can disturb peripheral positioning of envelope-bound heterochromatin domains and can therefore disrupt the long-term balance of chromatin organization [ 32 ]. Recent work highlights the important role of lamina-associated heterochromatin domains of the structural and functional maintenance of nuclear architecture [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy

Freyter

Al-razaq

Isermann

et al. 2022

Cells

View full text Add to dashboard Cite

Irreparable DNA damage following ionizing radiation (IR) triggers prolonged DNA damage response and induces premature senescence. Cellular senescence is a permanent state of cell-cycle arrest characterized by chromatin restructuring, altered nuclear morphology and acquisition of secretory phenotype, which contributes to senescence-related inflammation. However, the mechanistic connections for radiation-induced DNA damage that trigger these senescence-associated hallmarks are poorly understood. In our in vitro model of radiation-induced senescence, mass spectrometry-based proteomics was combined with high-resolution imaging techniques to investigate the interrelations between altered chromatin compaction, nuclear envelope destabilization and nucleo-cytoplasmic chromatin blebbing. Our findings confirm the general pathophysiology of the senescence-response, with disruption of nuclear lamin organization leading to extensive chromatin restructuring and destabilization of the nuclear membrane with release of chromatin fragments into the cytosol, thereby activating cGAS-STING-dependent interferon signaling. By serial block-face scanning electron microscopy (SBF-SEM) whole-cell datasets were acquired to investigate the morphological organization of senescent fibroblasts. High-resolution 3-dimensional (3D) reconstruction of the complex nuclear shape allows us to precisely visualize the segregation of nuclear blebs from the main nucleus and their fusion with lysosomes. By multi-view 3D electron microscopy, we identified nanotubular channels formed in lamin-perturbed nuclei of senescent fibroblasts; the potential role of these nucleo-cytoplasmic nanotubes for expulsion of damaged chromatin has to be examined.

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy

Freyter

Al-razaq

Isermann

et al. 2022

Cells

View full text Add to dashboard Cite

show abstract

“…The present results may lead to new perspectives on the actual role of w/w phase separation in the formation of organelles. As related subjects, it was recently found that the boundary constraints of the nucleolus and nuclear envelope play essential functions through micro-phase separation with multiple biomacromolecules [ 56 , 57 ] and that active and repressed chromatin separates from the nuclear interier and form a peripheral layer as obseved through live imaging [ 58 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

Higher-order structure of DNA determines its positioning in cell-size droplets under crowded conditions

Nishio

Yoshikawa

2021

PLoS ONE

View full text Add to dashboard Cite

Background It is becoming clearer that living cells use water/water (w/w) phase separation to form membraneless organelles that exhibit various important biological functions. Currently, it is believed that the specific localization of biomacromolecules, including DNA, RNA and proteins in w/w microdroplets is closely related to their bio-activity. Despite the importance of this possible role of micro segregation, our understanding of the underlying physico-chemical mechanism is still unrefined. Further research to unveil the underlying mechanism of the localization of macromolecules in relation to their steric conformation in w/w microdroplets is needed. Principal findings Single-DNA observation of genome-size DNA (T4 GT7 bacteriophage DNA; 166kbp) by fluorescence microscopy revealed that DNAs are spontaneously incorporated into w/w microdroplets generated in a binary aqueous polymer solution with polyethylene glycol (PEG) and dextran (DEX). Interestingly, DNAs with elongated coil and shrunken conformations exhibit Brownian fluctuation inside the droplet. On the other hand, tightly packed compact globules, as well as assemblies of multiple condensed DNAs, tend to be located near the interface in the droplet. Conclusion and significance The specific localization of DNA molecules depending on their higher-order structure occurs in w/w microdroplet phase-separation solution under a binary aqueous polymer solution. Such an aqueous solution with polymers mimics the crowded conditions in living cells, where aqueous macromolecules exist at a level of 30–40 weight %. The specific positioning of DNA depending on its higher-order structure in w/w microdroplets is expected to provide novel insights into the mechanism and function of membraneless organelles and micro-segregated particles in living cells.

show abstract

“…In wound healing and myocardial infarction, genome accumulation stimulates adaptation to DNA damage, mechanical stress, and inflammation [ 9 , 34 ]. Moreover, in polyploid giant cancer cells, multiple genomes confer resistance to chemo- and radiotherapy [ 23 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. These data are in agreement with previous observations of plant polyploid cells, indicating that multiple genomes can live under conditions under which diploid cells do not survive [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Ploidy-associated epigenetic regulation has attracted increasing attention because it enables genome reorganization and cell fate change in adverse environments and in response to extreme stress [ 39 , 41 , 42 , 50 ]. Moreover, this mode of regulation operating via ploidy-related epigenetic rearrangements is characteristic of carcinogenesis and resistance to therapy [ 42 , 43 ]. In this review, we extensively analyze the literature, which indicates that polyploidy provokes global genome reorganization via chromatin relaxation induced by stress-related Myc overexpression and ploidy-related architectural rearrangements.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

Anatskaya

Vinogradov

2022

IJMS

View full text Add to dashboard Cite

Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; and pathologies, including cardiovascular diseases, neurodegeneration, and cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying ploidy-related adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs of embryonality. Chromatin opening switches on genes with bivalent chromatin domains that promote adaptation via rapid induction in response to signals of stress or morphogenesis. Therefore, stress-associated polyploidy can activate Myc proto-oncogenes, which further promote chromatin opening. Moreover, Myc proto-oncogenes can trigger polyploidization de novo and accelerate genome accumulation in already polyploid cells. As a result of these cooperative effects, polyploidy can increase the ability of cells to search for adaptive states of cellular programs through gene regulatory network rewiring. This ability is manifested in epigenetic plasticity associated with traits of stemness, unicellularity, flexible energy metabolism, and a complex system of DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular repair pathways, and DNA damage-buffering ability. These three features can be considered important components of the increased adaptability of polyploid cells. The evidence presented here contribute to the understanding of the nature of stress resistance associated with ploidy and may be useful in the development of new methods for the prevention and treatment of cardiovascular and oncological diseases.

show abstract

Heterochromatin Networks: Topology, Dynamics, and Function (a Working Hypothesis)

Cited by 15 publications

References 142 publications

Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy

Nuclear Fragility in Radiation-Induced Senescence: Blebs and Tubes Visualized by 3D Electron Microscopy

Higher-order structure of DNA determines its positioning in cell-size droplets under crowded conditions

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring

Contact Info

Product

Resources

About