The LINC Between Mechanical Forces and Chromatin

Lityagina, Olga; Dobreva, Gergana

doi:10.3389/fphys.2021.710809

Cited by 24 publications

(15 citation statements)

References 63 publications

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“…The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, implicated in mechanical coupling between the cytoplasm and nucleoplasm, has been proposed to control chromatin organization and the epigenetic state of chromatin [ 1 , 2 , 3 , 4 ]. This complex consists of Nesprin proteins whose membrane-KASH domain is inserted into the outer nuclear membrane; their N-terminus associates with various cytoskeletal components.…”

Section: Introductionmentioning

confidence: 99%

The LINC Complex Inhibits Excessive Chromatin Repression

Pavlov

Unnikannan

Lorber

et al. 2023

Cells

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The Linker of Nucleoskeleton and Cytoskeleton (LINC) complex transduces nuclear mechanical inputs suggested to control chromatin organization and gene expression; however, the underlying mechanism is currently unclear. We show here that the LINC complex is needed to minimize chromatin repression in muscle tissue, where the nuclei are exposed to significant mechanical inputs during muscle contraction. To this end, the genomic binding profiles of Polycomb, Heterochromatin Protein1 (HP1a) repressors, and of RNA-Pol II were studied in Drosophila larval muscles lacking functional LINC complex. A significant increase in the binding of Polycomb and parallel reduction of RNA-Pol-II binding to a set of muscle genes was observed. Consistently, enhanced tri-methylated H3K9 and H3K27 repressive modifications and reduced chromatin activation by H3K9 acetylation were found. Furthermore, larger tri-methylated H3K27me3 repressive clusters, and chromatin redistribution from the nuclear periphery towards nuclear center, were detected in live LINC mutant larval muscles. Computer simulation indicated that the observed dissociation of the chromatin from the nuclear envelope promotes growth of tri-methylated H3K27 repressive clusters. Thus, we suggest that by promoting chromatin–nuclear envelope binding, the LINC complex restricts the size of repressive H3K27 tri-methylated clusters, thereby limiting the binding of Polycomb transcription repressor, directing robust transcription in muscle fibers.

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Section: Introductionmentioning

confidence: 99%

The LINC Complex Inhibits Excessive Chromatin Repression

Pavlov

Unnikannan

Lorber

et al. 2023

Cells

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“…Furthermore, studies have implicated a role for the nucleus in directly transducing a biomechanical signal via the linker of nucleoskeleton and cytoskeleton (LINC) complex [197]. The LINC complex, localised to the nuclear membrane, binds to all three cytoskeletal proteins and in particular to the intermediate filament lamin A which anchors chromatin to the nuclear lamina (comprising lamins A and C) [198] providing a structural pathway for force transmission from the cell surface to the chromatin [199]. As lamins A and C are located at the nuclear periphery, in addition to the nuclear interior, they associate with both hetero-and transcriptionally active euchromatin [200] providing a mechanism by which mechanical load can regulate gene transcription [201].…”

Section: Bidirectional Reciprocity Involves Alterations To the Ecm Due To Mechanically Mediated Cell Behavioursmentioning

confidence: 99%

Mechanical Cues: Bidirectional Reciprocity in the Extracellular Matrix Drives Mechano-Signalling in Articular Cartilage

Gilbert

Bonnet

Blain

2021

IJMS

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The composition and organisation of the extracellular matrix (ECM), particularly the pericellular matrix (PCM), in articular cartilage is critical to its biomechanical functionality; the presence of proteoglycans such as aggrecan, entrapped within a type II collagen fibrillar network, confers mechanical resilience underweight-bearing. Furthermore, components of the PCM including type VI collagen, perlecan, small leucine-rich proteoglycans—decorin and biglycan—and fibronectin facilitate the transduction of both biomechanical and biochemical signals to the residing chondrocytes, thereby regulating the process of mechanotransduction in cartilage. In this review, we summarise the literature reporting on the bidirectional reciprocity of the ECM in chondrocyte mechano-signalling and articular cartilage homeostasis. Specifically, we discuss studies that have characterised the response of articular cartilage to mechanical perturbations in the local tissue environment and how the magnitude or type of loading applied elicits cellular behaviours to effect change. In vivo, including transgenic approaches, and in vitro studies have illustrated how physiological loading maintains a homeostatic balance of anabolic and catabolic activities, involving the direct engagement of many PCM molecules in orchestrating this slow but consistent turnover of the cartilage matrix. Furthermore, we document studies characterising how abnormal, non-physiological loading including excessive loading or joint trauma negatively impacts matrix molecule biosynthesis and/or organisation, affecting PCM mechanical properties and reducing the tissue’s ability to withstand load. We present compelling evidence showing that reciprocal engagement of the cells with this altered ECM environment can thus impact tissue homeostasis and, if sustained, can result in cartilage degradation and onset of osteoarthritis pathology. Enhanced dysregulation of PCM/ECM turnover is partially driven by mechanically mediated proteolytic degradation of cartilage ECM components. This generates bioactive breakdown fragments such as fibronectin, biglycan and lumican fragments, which can subsequently activate or inhibit additional signalling pathways including those involved in inflammation. Finally, we discuss how bidirectionality within the ECM is critically important in enabling the chondrocytes to synthesise and release PCM/ECM molecules, growth factors, pro-inflammatory cytokines and proteolytic enzymes, under a specified load, to influence PCM/ECM composition and mechanical properties in cartilage health and disease.

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“…These and other mechanotransduction pathways have been extensively explored and reviewed ( Jaalouk and Lammerding, 2009 ; Martino et al, 2018 ; Wagh et al, 2021 ; Zuela-Sopilniak and Lammerding, 2022 ). Forces applied to the membrane can also directly influence the genetic programs that dictate the phenotypic response of the cell since the cytoskeletal network is linked to the nuclear structure containing chromatin and DNA through the linker of nucleoskeleton and cytoskeleton (LINC) complex ( Lombardi et al, 2011 ), which also has been reviewed extensively ( Lombardi and Lammerding, 2011 ; Bouzid et al, 2019 ; Lityagina and Dobreva, 2021 ; Wong et al, 2021 ). Although the mechanisms of mechanotransduction that mediate phenotypic plasticity have been well characterized in many systems, what is less known is how the mechanical environment alters cell fate and establishes a stable response, or memory.…”

Section: Introductionmentioning

confidence: 99%

“…In the case of cardiac cells also, there is recent literature that highlights such mechanical regulation of the epigenetic landscape and its importance in cardiomyocyte development and function ( Tingare et al, 2013 ; Stratton and McKinsey, 2016 ; Jarrell et al, 2019 ; Lityagina and Dobreva, 2021 ; Ross and Stroud, 2021 ; Powers and McCulloch, 2022 ). Connections from the cardiomyocyte nucleus to the external environment through microtubules and desmin intermediate filaments is required for the maintenance of the nuclear morphology and the loss of these connections results in aberrant gene expression and DNA damage ( Heffler et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Mechanically induced alterations in chromatin architecture guide the balance between cell plasticity and mechanical memory

Scott

Rafuse

Neu

2023

Front. Cell Dev. Biol.

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Phenotypic plasticity, or adaptability, of a cell determines its ability to survive and function within changing cellular environments. Changes in the mechanical environment, ranging from stiffness of the extracellular matrix (ECM) to physical stress such as tension, compression, and shear, are critical environmental cues that influence phenotypic plasticity and stability. Furthermore, an exposure to a prior mechanical signal has been demonstrated to play a fundamental role in modulating phenotypic changes that persist even after the mechanical stimulus is removed, creating stable mechanical memories. In this mini review, our objective is to highlight how the mechanical environment alters both phenotypic plasticity and stable memories through changes in chromatin architecture, mainly focusing on examples in cardiac tissue. We first explore how cell phenotypic plasticity is modulated in response to changes in the mechanical environment, and then connect the changes in phenotypic plasticity to changes in chromatin architecture that reflect short-term and long-term memories. Finally, we discuss how elucidating the mechanisms behind mechanically induced chromatin architecture that lead to cell adaptations and retention of stable mechanical memories could uncover treatment methods to prevent mal-adaptive permanent disease states.

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The LINC Between Mechanical Forces and Chromatin

Cited by 24 publications

References 63 publications

The LINC Complex Inhibits Excessive Chromatin Repression

The LINC Complex Inhibits Excessive Chromatin Repression

Mechanical Cues: Bidirectional Reciprocity in the Extracellular Matrix Drives Mechano-Signalling in Articular Cartilage

Mechanically induced alterations in chromatin architecture guide the balance between cell plasticity and mechanical memory

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