The secret life of chromatin tethers

Kiseleva, Anna A.; Poleshko, Andrey

doi:10.1002/1873-3468.14685

Cited by 5 publications

(4 citation statements)

References 67 publications

(118 reference statements)

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“…Consistent with this hypothesis, Lamin B Receptor (LBR) mediates at least in part the peripheral positioning of heterochromatin 63,64 and was shown to preferentially interact with supercoiled DNA 65 . Specific concentration of factors such as HP1 or modified histones could also mediate anchoring of boosting regions at the NL 22,66 .…”

Section: Discussionmentioning

confidence: 99%

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Genome - nuclear lamina interactions are multivalent and cooperative

Dauban,

Eder,

de Haas

et al. 2024

Preprint

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Lamina-associated domains (LADs) are megabase-sized genomic regions that interact with the nuclear lamina (NL). It is not yet understood how their interactions with the NL are encoded in their DNA. Here, we designed an efficient LAD “scrambling” approach, based on transposon-mediated local hopping of loxP recombination sites, to generate series of large deletions and inversions that span LADs and flanking sequences. Mapping of NL interactions in these rearrangements revealed that a single LAD contacts the NL through multiple regions that act cooperatively or redundantly; some have more affinity for the NL than others and can pull neighbouring sequences to the NL. Genes drawn towards the NL showed often, but not always, reduced expression and increased H3K9me3 levels. Furthermore, neighbouring LADs can cooperatively interact with the NL when placed close enough to each other. These results elucidate principles that govern the positioning of megabase-sized genomic regions inside the cell nucleus.HighlightsEfficient generation of LAD rearrangements by transposon hopping ofloxPelements.NL interactions are multivalent, with some subregions being more potent tethers than others.LADs can cooperate to promote their association to the NL.Changes in NL association are often accompanied by changes in gene activity and H3K9me3.

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Section: Discussionmentioning

confidence: 99%

“…How are LAD-NL interactions instructed by LAD DNA ? Although several chromatin and NL proteins have been identified that may mediate NL-LAD interactions 21,22 , a major unresolved question is how these interactions are encoded within LAD DNA. This is particularly intriguing considering the enormous size of LADs.…”

Section: Introductionmentioning

confidence: 99%

Genome - nuclear lamina interactions are multivalent and cooperative

Dauban,

Eder,

de Haas

et al. 2024

Preprint

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“…The last term captures the interaction between chromatin and the nuclear lamina, which leads to the formation of LADs along the nuclear periphery. In-vivo, the interactions between chromatin and the nuclear lamina are orchestrated by a diverse set of chromatin anchoring proteins, such as LAP2β, LBR, emerin and PRR14, associated with the inner nuclear membrane and the nuclear lamina [10,17]. While these interactions can be individually incorporated by capturing the strength of each anchoring protein associated with the lamina and the nuclear membrane, as a first approximation we assume these to be the same.…”

Section: Driving Forces For the Spatiotemporal Evolution Of Chromatinmentioning

confidence: 99%

Revealing the Biophysics of Lamina-Associated Domain Formation by Integrating Theoretical Modeling and High-Resolution Imaging

Dhankhar,

Guo,

Kant

et al. 2024

Preprint

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The interactions between chromatin and the nuclear lamina orchestrate cell type-specific gene activity by forming lamina-associated domains (LADs) which preserve cellular characteristics through gene repression. However, unlike the interactions between chromatin segments, the strength of chromatin-lamina interactions and their dependence on cellular environment are not well understood. Here, we develop a theory to predict the size and shape of peripheral heterochromatin domains by considering the energetics of chromatin-chromatin interactions, the affinity between chromatin and the nuclear lamina and the kinetics of methylation and acetylation9in human mesenchymal stem cells (hMSCs). Through the analysis of super-resolution images of peripheral heterochromatin domains using this theoretical framework, we determine the nuclear lamina-wide distribution of chromatin-lamina affinities. We find that the extracted affinity is highly spatially heterogeneous and shows a bimodal distribution, indicating regions along the lamina with strong chromatin binding and those exhibiting vanishing chromatin affinity interspersed with some regions exhibiting a relatively diminished chromatin interactions, in line with the presence of structures such as nuclear pores. Exploring the role of environmental cues on peripheral chromatin, we find that LAD thickness increases when hMSCs are cultured on a softer substrate, in correlation with contractility-dependent translocation of histone deacetylase 3 (HDAC3) from the cytosol to the nucleus. In soft microenvironments, chromatin becomes sequestered at the nuclear lamina, likely due to the interactions of HDAC3 with the chromatin anchoring protein LAP2β,increasing chromatin-lamina affinity, as well as elevated levels of the intranuclear histone methylation. Our findings are further corroborated by pharmacological interventions that inhibit contractility, as well as by manipulating methylation levels using epigenetic drugs. Notably, in the context of tendinosis, a chronic condition characterized by collagen degeneration, we observed a similar increase in the thickness of peripheral chromatin akin to that of cells cultured on soft substrates consistent with theoretical predictions. Our findings underscore the pivotal role of the microenvironment in shaping genome organization and highlight its relevance in pathological conditions.

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“…The article by Capelson [10] explores how nucleoporins affect gene expression, focusing on the fact that a subset of nucleoporins can localize to the nuclear interior and interact with chromatin through a variety of associated chromatin‐modulating proteins, thus contributing to the gene expression control on multiple levels. The role of the nuclear periphery in the organization of heterochromatin in mammals is discussed by Kiseleva and Poleshko [11], while Buxboim et al . [12] provide the latest insights into the structural organization of the lamina, in particular its major constituents, the nuclear lamins.…”

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confidence: 99%