The SUN1 splicing variants SUN1_888 and SUN1_916 differentially regulate nucleolar structure

Satomi, Erina; Ueda, Masako; Katahira, Jun; Hieda, Miki

doi:10.1111/gtc.12807

Cited by 5 publications

(5 citation statements)

References 57 publications

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“…Previous studies have shown that depletion of Sun1/2 reduces tethering of chromosomes to the nuclear envelope 31, 39, 40 , alters nucleolus morphology 41 , and increases trimethylated K9 histone (H3K9me3) levels in hTERT-RPE1 and MCF10A cells 42 . Our results show similar trends as Sun1/2 depletion in MSCs increased both H3K9me3 protein levels and number of H3K9me3 heterochromatic foci while no H3K9me3 protein levels or foci number increases were observed under dnKASH expression.…”

Section: Discussionmentioning

confidence: 99%

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

Goelzer

Howard

Zavala

et al. 2022

Preprint

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Mechanical signals regulate adipogenic differentiation of mesenchymal stem cells (MSCs). Critical to the mechano-regulation of MSCs, Linker of the Nucleoskeleton and Cytoskeleton (LINC) complexes are integral to both nucleo-cytoskeletal signal transduction and structural integrity of the nucleus. The LINC complex is made of Nesprin proteins that associate with the cytoskeleton on the outer nuclear membrane (ONM) and Sun proteins that bound to nuclear lamina and chromatin at the inner nuclear membrane (INM). In addition to their role in the LINC complex function, depletion of Sun1/2 effects chromosomal tethering to the nuclear envelope, nuclear morphology, and chromatin organization. Suggesting that Sun1/2 proteins may regulate chromatin organization and adipogenic differentiation independent of the LINC complex mediated nucleo-cytoskeletal connectivity. To test this hypothesis Sun1/2 depletion was compared to expression of a dominant-negative KASH (dnKASH) domain to decouple nucleus from cytoskeleton by inhibiting Nesprin-SUN association. Sun1/2 depletion inhibited fat droplet formation and production of adipogenic proteins such as Adipoq, which were supported by RNA-seq showing decreased adipogensis. In contrast dnKASH responded oppositely, increasing fat droplet formation, Adipoq and adipogenic gene expression. At the chromatin level, Sun1/2 depletion increased H3K9me3 levels, increased H3K9me3 foci count, and enrichment on Adipoq. No increase of H3K9me3 levels, foci count, or increased H3K9me3 enrichment on Adipoq was found during dnKASH expression. We conclude that physically decoupling of the LINC complex via dnKASH accelerates adipogenesis and that depletion of Sun1/2 increases heterochromatin accrual and inhibits adipogenesis independent of the LINC complex function.

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Section: Discussionmentioning

confidence: 99%

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

Goelzer

Howard

Zavala

et al. 2022

Preprint

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“…The nucleolus harbors a tripartite architecture with three distinct areas: the inner part of the nucleolus is called the Fibrillar Centre (FC), the outer is the Granular Centre (GC), and in-between them is the Dense Fibrillar Component (DFC) [41]. Loss of the integral nuclear envelope protein SUN1 alters this structure [42,43]. The main function of a nucleolus is to assemble the transcription and processing machineries that are responsible for generating ribosome subunits.…”

Section: Nuclear Bodiesmentioning

confidence: 99%

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

Corvaisier

Alvarado-Kristensson

2020

Cancers

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The nuclear architecture describes the organization of the various compartments in the nucleus of eukaryotic cells, where a plethora of processes such as nucleocytoplasmic transport, gene expression, and assembly of ribosomal subunits occur in a dynamic manner. During the different phases of the cell cycle, in post-mitotic cells and after oncogenic transformation, rearrangements of the nuclear architecture take place, and, among other things, these alterations result in reorganization of the chromatin and changes in gene expression. A member of the tubulin family, γtubulin, was first identified as part of a multiprotein complex that allows nucleation of microtubules. However, more than a decade ago, γtubulin was also characterized as a nuclear protein that modulates several crucial processes that affect the architecture of the nucleus. This review presents the latest knowledge regarding changes that arise in the nuclear architecture of healthy cells and under pathological conditions and, more specifically, considers the particular involvement of γtubulin in the modulation of the biology of the nuclear compartment.

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“…Caragine et al recently made the interesting observation that the nucleoplasm has an active (ATP dependent) contribution to nucleolar fusion and that disturbing chromatin dynamics altered nucleolar number and size(54). Depletion of components of the nuclear membrane LINC (linker of nucleoskeleton and cytoskeleton) complex and damage of rDNA have also been shown to regulate nucleolar number and morphology(55–57). Future studies will involve exploration of the role of TIF-IA in these alternative pathways to nucleolar fusion.…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of components of the nuclear membrane LINC (linker of nucleoskeleton and cytoskeleton) complex and damage of rDNA have also been shown to regulate nucleolar number and morphology (55)(56)(57). Future studies will involve exploration of the role of TIF-IA in these alternative pathways to nucleolar fusion.…”

Section: Tif-ia Nucleolar Fusion and Nf-b Pathway Activationmentioning

confidence: 99%

Identification of a P62-TIF-IA axis that drives nucleolar fusion and the senescence associated secretory phenotype

Thoms,

Brant,

Duckett

et al. 2023

Preprint

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Two key characteristics of senescent cells are nucleolar fusion and secretion of a plethora of pro-inflammatory cytokines called the senescence-associated secretory phenotype (SASP). The SASP is dependent on NF-κB but the initial trigger, and links with nucleoli, are unclear. Using multiplein vitroandin vivomodels, we show that an early response to oncogene- and therapy-induced senescence (OIS and TIS) is nuclear/nucleolar accumulation of the PolI complex component, TIF-IA. This accumulation is essential for nucleolar fusion, the SASP and senescence, independent of rDNA transcription. We show that in steady state, TIF-IA is targeted for autophagic degradation by the p62 cargo receptor and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts the p62-TIF-IA interaction. In mice, TIF-IA accumulates in colonic mucosa with age, which is further enhanced in thenfkb1-/-model of accelerated ageing. Together, these results reveal a p62-TIF-IA nucleolar stress axis that regulates the SASP and senescence, and that warrants further investigation as an anti-ageing target.

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The SUN1 splicing variants SUN1_888 and SUN1_916 differentially regulate nucleolar structure

Cited by 5 publications

References 57 publications

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

Depletion of Sun1/2 induces heterochromatin accrual in mesenchymal stem cells during adipogenesis

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

Identification of a P62-TIF-IA axis that drives nucleolar fusion and the senescence associated secretory phenotype

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