The condensation of HP1-α/Swi6 imparts nuclear stiffness

Williams, Jessica F.; Surovtsev, Ivan V.; Schreiner, Sarah M.; Nguyen, Hang; Hu, Yan; Mochrie, S. G. J.; King, Megan C.

doi:10.1101/2020.07.02.184127

Cited by 14 publications

(12 citation statements)

References 92 publications

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“…59 These factors alone or together could shape nuclear architecture and chromatin relocation. However, our findings are in agreement with the literature showing that the resulting alteration in H3K9me3heterochromatin organization increases local apparent viscosity near the periphery, 60 and an increase in viscosity is due to altered chromatin structure potentially from a condensed chromatin state in the nucleoplasm. 61 Further studies on nuclear softening 41,62 and epigenetic memory response 63 due to aligned configurations could provide exciting insights on chromatin organization.…”

Section: Resultssupporting

confidence: 93%

Dynamic Heterochromatin States in Anisotropic Nuclei of Cells on Aligned Nanofibers

et al. 2022

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The cancer cell nucleus deforms as it invades the interstitial spaces in tissues and the tumor microenvironment. While alteration of the chromatin structure in a deformed nucleus is expected and documented, the chromatin structure in the nuclei of cells on aligned matrices has not been elucidated. In this work we elucidate the spatiotemporal organization of heterochromatin in the elongated nuclei of cells on aligned nanofibers with stimulated emission depletion nanoscopy and fluorescence correlation spectroscopy. We show that the anisotropy of nuclei is sufficient to drive H3K9me3-heterochromatin alterations, with enhanced H3K9me3 nanocluster compaction and aggregation states that otherwise are indistinguishable from diffraction-limited microscopy. We interrogated the higher-order heterochromatin structures within major chromatin compartments in anisotropic nuclei and discovered a wider spatial dispersion of nanodomain clusters in the nucleoplasm and condensed larger nanoclusters near the periphery and pericentromeric heterochromatin. Upon examining the spatiotemporal dynamics of heterochromatin in anisotropic nuclei, we observed reduced mobility of the constitutive heterochromatin mark H3K9me3 and the associated heterochromatin protein 1 (HP1α) at the nucleoplasm and periphery regions, correlating with increased viscosity and changes in gene expression. Since heterochromatin remodeling is crucial to genome integrity, our results reveal an unconventional H3K9me3 heterochromatin distribution, providing cues to an altered chromatin state due to perturbations of the nuclei in aligned fiber configurations.

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Section: Resultssupporting

confidence: 93%

Dynamic Heterochromatin States in Anisotropic Nuclei of Cells on Aligned Nanofibers

et al. 2022

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“…Together, these observations suggest a complex physical picture that is dictated by both HP1α’s self-interaction and chromatin binding capabilities, in addition to length, concentration, and phase behavior of the chromatin itself ( Gibson et al, 2019 ; Maeshima et al, 2021 ; Strickfaden et al, 2020 ). The material state and categorization of the phase transition of HP1α-rich heterochromatin in vivo have been debated ( Erdel et al, 2020 ; Larson et al, 2017 ; Strom et al, 2017 ; Williams et al, 2020 ), and the underlying chromatin may be ‘solid-like’ ( Strickfaden et al, 2020 ), so further work is necessary to completely understand the interplay of these components in determining phase behavior and mechanics of the interphase nucleus.…”

Section: Discussionmentioning

confidence: 99%

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics

Strom

Biggs

Banigan

et al. 2021

eLife

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Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1α (CBX5) is unknown. We used a novel HP1α auxin-inducible degron human cell line to rapidly degrade HP1α. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1α is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1αI165E indicate that chromatin crosslinking via HP1α dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1α similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1α is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions.

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“…DNA–protein co-condensation not only provides mechanisms to facilitate enhancer–promoter contacts, but could also play a more general role in DNA compaction and maintenance of bulk chromatin rigidity in processes such as mitotic chromatid compaction 24 , and the formation of chromatin compartments 8,25,26 . Owing to the tension-dependent nature of DNA–protein co- condensation, our work suggests that these forces could play a key and, as yet, underappreciated role in genome organization and transcriptional initiation.…”

Section: Main Textmentioning

confidence: 99%

Force generation by protein-DNA co-condensation

Quail

Golfier

Elsner

et al. 2020

Preprint

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SummaryCapillary forces are driven by interactions between liquids and surfaces1. These forces are crucial for many processes ranging from biology and physics to engineering, such as the motion of aquatic insects on the surface of water2, modulation of the material properties of spider silk3,4, and self-assembly of small objects and microstructures5. Recent studies have shown that cells assemble biomolecular condensates in a manner similar to phase separation6. In the nucleus, these condensates are thought to drive transcription7–10, heterochromatin formation11,12, nucleolus assembly13,14, and DNA repair15,16. Here, we test if the interaction between liquid-like condensates and chromatin generates capillary forces, which might play a role in bringing distant regulatory elements of DNA together, a key step in transcriptional regulation. We combine quantitative microscopy, in vitro reconstitution, and theory to show that the pioneer transcription factor FoxA1 mediates the condensation of a DNA-protein phase via a mesoscopic first-order phase transition. Surprisingly, after nucleation, capillary forces drive growth of this phase by pulling non-condensed DNA. Altering the tension on the DNA strand enlarges or dissolves the condensates, revealing their mechanosensitive nature. These findings show that DNA condensation mediated by transcription factors could bring distant regions of DNA in close proximity using capillary forces. Our work suggests that the physics of DNA and protein condensation driven by capillary forces provides a general regulatory principle for chromatin organization.

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The condensation of HP1-α/Swi6 imparts nuclear stiffness

Cited by 14 publications

References 92 publications

Dynamic Heterochromatin States in Anisotropic Nuclei of Cells on Aligned Nanofibers

Dynamic Heterochromatin States in Anisotropic Nuclei of Cells on Aligned Nanofibers

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics

Force generation by protein-DNA co-condensation

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