Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage

Nava, Michele M.; Miroshnikova, Yekaterina A.; Biggs, Leah C.; Whitefield, Daniel B.; Metge, Franziska; Bouças, Jorge; Vihinen, Helena; Jokitalo, Eija; Li, Xinping; García-Arcos, Juan Manuel; Hoffmann, Bernd; Merkel, Rudolf; Niessen, Carien M.; Dahl, Kris Noel; Wickström, Sara A.

doi:10.1016/j.cell.2020.03.052

Cited by 401 publications

(466 citation statements)

References 86 publications

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“…It is possible that, in ATR-defective cells, deregulated topological and condensation activities may cause nuclear membranes invaginations and ruptures, nuclear fragmentation, and micronuclei formation; the heterochromatic and heavily condensed chromatin could instead result from the deregulation of the NRD complex 46 . Recent observations 47 showed that H3K9 trimethylation marked heterochromatin levels rearrange in response to mechanical stress at the NE and the recovery of the nucleus. In this scenario, our finding that a longterm depletion of ATR accumulates hypercompacted chromatin at the nuclear periphery and elevated levels of H3K9 trimethylation may therefore reflect the inability of ATR-depleted cells to properly recover from nuclear stress.…”

Section: Discussionmentioning

confidence: 99%

ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration

Kidiyoor

Bastianello

et al. 2020

Nat Commun

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ATR responds to mechanical stress at the nuclear envelope and mediates envelope-associated repair of aberrant topological DNA states. By combining microscopy, electron microscopic analysis, biophysical and in vivo models, we report that ATR-defective cells exhibit altered nuclear plasticity and YAP delocalization. When subjected to mechanical stress or undergoing interstitial migration, ATR-defective nuclei collapse accumulating nuclear envelope ruptures and perinuclear cGAS, which indicate loss of nuclear envelope integrity, and aberrant perinuclear chromatin status. ATR-defective cells also are defective in neuronal migration during development and in metastatic dissemination from circulating tumor cells. Our findings indicate that ATR ensures mechanical coupling of the cytoskeleton to the nuclear envelope and accompanying regulation of envelope-chromosome association. Thus the repertoire of ATR-regulated biological processes extends well beyond its canonical role in triggering biochemical implementation of the DNA damage response.

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Section: Discussionmentioning

confidence: 99%

ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration

Kidiyoor

Bastianello

et al. 2020

Nat Commun

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“…However, it is less obvious what mechanism would affect the transcription of nearby genes in the absence of an intermediate effect on genome organisation. Increased levels of DNA damage may be a contributing factor (Nava et al, 2020). Indeed, we have previously shown that γH2AX levels are increased in bone marrow cells from Suv39DKO chimeric mice.…”

Section: Discussionmentioning

confidence: 91%

“…Our findings here using our unique model of heterochromatin loss in primary immune cells complement several recent papers in different models and systems. In particular, a recent study used mechanical stress to disrupt heterochromatin stability in skin epidermis stem/progenitor cells (Nava et al, 2020). They also found a predominant down-regulation of gene expression, reduced lamina-association of heterochromatin domains, but were unable to find a correlation between H3K9me3-regulated regions and gene transcriptional changes (Nava et al, 2020).…”

Section: Discussionmentioning

confidence: 98%

“…In particular, a recent study used mechanical stress to disrupt heterochromatin stability in skin epidermis stem/progenitor cells (Nava et al, 2020). They also found a predominant down-regulation of gene expression, reduced lamina-association of heterochromatin domains, but were unable to find a correlation between H3K9me3-regulated regions and gene transcriptional changes (Nava et al, 2020). A separate study examined the formation of senescence-associated heterochromatin foci (SAHF) in the oncogene-induced senescence of fibroblast cells where they found a gain of interactivity within 3MB of a newly formed heterochromatin domain (Sati et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

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Suv39h-catalysed H3K9me3 is critical for euchromatic genome organisation and the maintenance of gene transcription

Keenan

Coughlan

Iannarella

et al. 2020

Preprint

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H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both Suv39h1 and Suv39h2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyse heterochromatic H3K9me3 deposition. Unexpectedly, we reveal a predominant repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (DNaseI-accessible, H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) regions. Examination of the 3D nucleome reveals that transcriptomic dysregulation occurs in euchromatic regions close to the nuclear periphery in 3-dimensional space. Moreover, this transcriptomic dysregulation is highly correlated with altered 3-dimensional genome organization in Suv39DKO cells. Together, our results suggest that the nuclear lamina-tethering of Suv39-dependent H3K9me3 domains provides an essential scaffold to support euchromatic genome organisation and the maintenance of gene transcription for healthy cellular function.

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“…in response to deformation [154]. As the models used to interpret data were all based on assumptions on the contributions of the various components of the cell, the cell properties varied substantially between the studies, suggesting differences in how the results of different methods were obtained or analyzed [155].…”

Section: Powerful Tools For Assessing Cell Mechanicanical Properties mentioning

confidence: 99%

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

Varlet

Helfer

Badens

2020

Cells

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Laminopathies are rare and heterogeneous diseases affecting one to almost all tissues, as in Progeria, and sharing certain features such as metabolic disorders and a predisposition to atherosclerotic cardiovascular diseases. These two features are the main characteristics of the adipose tissue-specific laminopathy called familial partial lipodystrophy type 2 (FPLD2). The only gene that is involved in FPLD2 physiopathology is the LMNA gene, with at least 20 mutations that are considered pathogenic. LMNA encodes the type V intermediate filament lamin A/C, which is incorporated into the lamina meshwork lining the inner membrane of the nuclear envelope. Lamin A/C is involved in the regulation of cellular mechanical properties through the control of nuclear rigidity and deformability, gene modulation and chromatin organization. While recent studies have described new potential signaling pathways dependent on lamin A/C and associated with FPLD2 physiopathology, the whole picture of how the syndrome develops remains unknown. In this review, we summarize the signaling pathways involving lamin A/C that are associated with the progression of FPLD2. We also explore the links between alterations of the cellular mechanical properties and FPLD2 physiopathology. Finally, we introduce potential tools based on the exploration of cellular mechanical properties that could be redirected for FPLD2 diagnosis.

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Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage

Cited by 401 publications

References 86 publications

ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration

ATR is essential for preservation of cell mechanics and nuclear integrity during interstitial migration

Suv39h-catalysed H3K9me3 is critical for euchromatic genome organisation and the maintenance of gene transcription

Molecular and Mechanobiological Pathways Related to the Physiopathology of FPLD2

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