Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies

Liu, Sunny Yang; Ikegami, Kohta

doi:10.1080/19491034.2020.1832734

Cited by 50 publications

(61 citation statements)

References 149 publications

(192 reference statements)

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“…Diseases may be due to mutations or altered expression of alleles, the mechanical stability of the nucleus, or cell cycle regulation. However, the molecular mechanisms that give rise to these diseases and whether pathogen infection may modulate the nuclear structure and contribute to the pathogenesis remain poorly understood [ 10 , 11 ].…”

Section: The Structure and Function Of The Nuclear Envelopementioning

confidence: 99%

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Lee

Chen

2021

Viruses

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The nuclear envelope (NE) of eukaryotic cells has a highly structural architecture, comprising double lipid-bilayer membranes, nuclear pore complexes, and an underlying nuclear lamina network. The NE structure is held in place through the membrane-bound LINC (linker of nucleoskeleton and cytoskeleton) complex, spanning the inner and outer nuclear membranes. The NE functions as a barrier between the nucleus and cytoplasm and as a transverse scaffold for various cellular processes. Epstein–Barr virus (EBV) is a human pathogen that infects most of the world’s population and is associated with several well-known malignancies. Within the nucleus, the replicated viral DNA is packaged into capsids, which subsequently egress from the nucleus into the cytoplasm for tegumentation and final envelopment. There is increasing evidence that viral lytic gene expression or replication contributes to the pathogenesis of EBV. Various EBV lytic proteins regulate and modulate the nuclear envelope structure in different ways, especially the viral BGLF4 kinase and the nuclear egress complex BFRF1/BFRF2. From the aspects of nuclear membrane structure, viral components, and fundamental nucleocytoplasmic transport controls, this review summarizes our findings and recently updated information on NE structure modification and NE-related cellular processes mediated by EBV.

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Section: The Structure and Function Of The Nuclear Envelopementioning

confidence: 99%

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Lee

Chen

2021

Viruses

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“…Lamin A/C is highly phosphorylated during mitosis 45 . The phosphorylation of Lamin A/C at serine 22 (pSer22) is a well-studied phosphorylation site 45 . It is known that during mitosis pSer22 results in degradation of Lamin A/C 46 .…”

Section: Resultsmentioning

confidence: 99%

Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues

et al. 2021

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The levels of nuclear protein Lamin A/C are crucial for nuclear mechanotransduction. Lamin A/C levels are known to scale with tissue stiffness and extracellular matrix levels in mesenchymal tissues. But in epithelial tissues, where cells lack a strong interaction with the extracellular matrix, it is unclear how Lamin A/C is regulated. Here, we show in epithelial tissues that Lamin A/C levels scale with apico-basal cell compression, independent of tissue stiffness. Using genetic perturbations in Drosophila epithelial tissues, we show that apico-basal cell compression regulates the levels of Lamin A/C by deforming the nucleus. Further, in mammalian epithelial cells, we show that nuclear deformation regulates Lamin A/C levels by modulating the levels of phosphorylation of Lamin A/C at Serine 22, a target for Lamin A/C degradation. Taken together, our results reveal a mechanism of Lamin A/C regulation which could provide key insights for understanding nuclear mechanotransduction in epithelial tissues.

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“…Unravelling the transcriptional regulation that LMNA serves in SuSC’s will likely arise from integration of heterochromatin anchoring and the ability of phosphorylated Lamin to interact with epigenetic modifiers and transcription factors. While mutations in some phosphorylation sites (S222) cause precocious expression of some genes, LMNA can also promote enhancer silencing through DNA modifications 94 55 95 96. In skeletal development, the genetic networks downstream of Runx2 are equally complex as Runx2 is also a transcriptional activator and repressor whose activity is partly dependent on nuclear dynamics, (e.g.…”

Section: Discussionmentioning

confidence: 99%

Tissue scale properties of the extracellular matrix regulates nuclear shape, organisation and fate in the embryonic midline sutures

Alves-Afonso

Ryan

Lahola-Chomiak

et al. 2021

Preprint

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Balancing self-renewal and differentiation is a key feature of every stem cell niche and one that is tuned by mechanical interactions of cells with their neighbors and surrounding extracellular matrix. The fibrous stem cell niches that develop as sutures between skull bones must balance the complex extracellular environment that emerges to define them with self-renewal and bone production. Here, we address the role for physical stimuli in suture development by probing the relationship between nuclear shape, organization and gene expression in response to a developing collagen network in embryonic midline sutures. This work complements genetic approaches used to study sutures and provides the first quantitative analyses of physical structure in these sutures. By combining multiple imaging modalities with novel shape description, in addition to network analysis methods, we find the early emergence of a complex extracellular collagen network to have an important role in regulating morphogenesis and cell fate. We show that disrupted collagen crosslinking can alter ECM organization of midline sutures as well as stimulate expression of bone differentiation markers. Further, our findings suggest that in vivo, skeletal tissues can uncouple the response of the nuclear lamina from collagen mediated tissue stiffening seen in vitro. Our findings highlight a crucial relationship between the cellular microenvironment, tissue stiffness and geometry with gene expression in normal development and maintenance of progenitor fate in embryonic sutures.

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Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies

Cited by 50 publications

References 149 publications

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Conquering the Nuclear Envelope Barriers by EBV Lytic Replication

Apico-basal cell compression regulates Lamin A/C levels in epithelial tissues

Tissue scale properties of the extracellular matrix regulates nuclear shape, organisation and fate in the embryonic midline sutures

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