Liquid chromatin Hi-C characterizes compartment-dependent chromatin interaction dynamics

Belaghzal, Houda; Borrman, Tyler; Stephens, Andrew D.; Lafontaine, Denis L.; Venev, Sergey V.; Weng, Zhiping; Marko, John F.; Dekker, Job

doi:10.1038/s41588-021-00784-4

Cited by 95 publications

(101 citation statements)

References 73 publications

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“…Alternatively, HP1α homodimerization and/or higher-order oligomerization could directly impact mechanics through physical bridging of two chromatin fibers, resulting in crosslinking of DNA or H3K9me 2,3 -marked nucleosomes ( Canzio et al, 2011 ; Cheutin et al, 2003 ; Machida et al, 2018 ). Consistent with this possibility, chromatin crosslinks have been suggested to be a key element of chromatin organization and mechanics ( Banigan et al, 2017 ; Belaghzal et al, 2021 ; Lionetti et al, 2020 ; Stephens et al, 2017 ). The capacity of HP1α to drive liquid-liquid phase separation ( Larson et al, 2017 ; Strom et al, 2017 ) could also contribute to altered chromatin organization and mechanics, given the emerging evidence for links between phase separation and nuclear mechanics ( Shin et al, 2018 ).…”

Section: Introductionmentioning

confidence: 78%

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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Section: Introductionmentioning

confidence: 78%

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

Strom

Biggs

Banigan

et al. 2021

eLife

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“…It has been recently proposed that chromatins, which are long polymers, behave as block copolymers (Belanghzal et al, 2021;Hildebrand & Dekker, 2020) and our work develops the concept that RNPs can function as block copolymers to form highly ordered RNP micelles in cells. Further work is needed to elucidate the molecular details (e.g., the components, including RBPs, and the RNA sequence and structural elements) of the RNP block copolymers.…”

Section: Discussionmentioning

confidence: 94%

Paraspeckles are constructed as block copolymer micelles

et al. 2021

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Paraspeckles are constructed by NEAT1_2 architectural long noncoding RNAs. Their characteristic cylindrical shapes, with highly ordered internal organization, distinguish them from typical liquid-liquid phase-separated condensates. We experimentally and theoretically investigated how the shape and organization of paraspeckles are determined. We identified the NEAT1_2 RNA domains responsible for shell localization of the NEAT1_2 ends, which determine the characteristic internal organization. Using the soft matter physics, we then applied a theoretical framework to understand the principles that determine NEAT1_2 organization as well as shape, number, and size of paraspeckles. By treating paraspeckles as amphipathic block copolymer micelles, we could explain and predict the experimentally observed behaviors of paraspeckles upon NEAT1_2 domain deletions or transcriptional modulation. Thus, we propose that paraspeckles are block copolymer micelles assembled through a type of microphase separation, micellization. This work provides an experimentbased theoretical framework for the concept that ribonucleoprotein complexes (RNPs) can act as block copolymers to form RNAscaffolding biomolecular condensates with optimal sizes and structures in cells.

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“…Highresolution Hi-C maps have enabled the discovery of an additional layer of organization that splits A/B compartments into 5 subcompartments 14 . These were not only shown to exhibit Mega-domain strength distinct interaction patterns but additionally displayed specific patterns of chromatin modifications 14 , nuclear positioning 56,57 , and chromatin interaction stability 58 .…”

Section: Esrrb Zfp42mentioning

confidence: 99%

Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation

et al. 2021

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A hallmark of chromosome organization is the partition into transcriptionally active A and repressed B compartments, and into topologically associating domains (TADs). Both structures were regarded to be absent from the inactive mouse X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC reprogramming system and high-resolution Hi-C to produce a time course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we observe A/B-like compartments on the inactive X harbouring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, concomitant with downregulation of Xist. Importantly, we find that TAD formation precedes transcription and initiates from Xist-poor compartments. Here, we show that TAD formation and transcriptional reactivation are causally independent during X-reactivation while establishing Xist as a common denominator.

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Liquid chromatin Hi-C characterizes compartment-dependent chromatin interaction dynamics

Cited by 95 publications

References 73 publications

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

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

Paraspeckles are constructed as block copolymer micelles

Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation

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