SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina

Abstract Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of self-propagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin-associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression and promotes L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new functional link of the nuclear lamina with transcriptional repression.

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OASIS/CREB3L1 is a factor that responds to nuclear envelope stress

Cell Death Discovery ◽

10.1038/s41420-021-00540-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yasunao Kamikawa ◽

Atsushi Saito ◽

Koji Matsuhisa ◽

Masayuki Kaneko ◽

Rie Asada ◽

...

Keyword(s):

Cell Cycle ◽

Endoplasmic Reticulum ◽

Nuclear Envelope ◽

Genome Instability ◽

Nuclear Lamina ◽

Nuclear Deformation ◽

Membrane Domain ◽

Stress Response Pathway ◽

Envelope Stress ◽

Genome Activity

AbstractThe nuclear envelope (NE) safeguards the genome and is pivotal for regulating genome activity as the structural scaffold of higher-order chromatin organization. NE had been thought as the stable during the interphase of cell cycle. However, recent studies have revealed that the NE can be damaged by various stresses such as mechanical stress and cellular senescence. These types of stresses are called NE stress. It has been proposed that NE stress is closely related to cellular dysfunctions such as genome instability and cell death. Here, we found that an endoplasmic reticulum (ER)-resident transmembrane transcription factor, OASIS, accumulates at damaged NE. Notably, the major components of nuclear lamina, Lamin proteins were depleted at the NE where OASIS accumulates. We previously demonstrated that OASIS is cleaved at the membrane domain in response to ER stress. In contrast, OASIS accumulates as the full-length form to damaged NE in response to NE stress. The accumulation to damaged NE is specific for OASIS among OASIS family members. Intriguingly, OASIS colocalizes with the components of linker of nucleoskeleton and cytoskeleton complexes, SUN2 and Nesprin-2 at the damaged NE. OASIS partially colocalizes with BAF, LEM domain proteins, and a component of ESCRT III, which are involved in the repair of ruptured NE. Furthermore, OASIS suppresses DNA damage induced by NE stress and restores nuclear deformation under NE stress conditions. Our findings reveal a novel NE stress response pathway mediated by OASIS.

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Nuclear envelope rupture is induced by actin-based nucleus confinement

The Journal of Cell Biology ◽

10.1083/jcb.201603053 ◽

2016 ◽

Vol 215 (1) ◽

pp. 27-36 ◽

Cited By ~ 108

Author(s):

Emily M. Hatch ◽

Martin W. Hetzer

Keyword(s):

Nuclear Envelope ◽

Cancer Cells ◽

Nuclear Membrane ◽

Nuclear Lamina ◽

Membrane Stability ◽

Linc Complex ◽

Actin Bundles ◽

In Cells

Repeated rounds of nuclear envelope (NE) rupture and repair have been observed in laminopathy and cancer cells and result in intermittent loss of nucleus compartmentalization. Currently, the causes of NE rupture are unclear. Here, we show that NE rupture in cancer cells relies on the assembly of contractile actin bundles that interact with the nucleus via the linker of nucleoskeleton and cytoskeleton (LINC) complex. We found that the loss of actin bundles or the LINC complex did not rescue nuclear lamina defects, a previously identified determinant of nuclear membrane stability, but did decrease the number and size of chromatin hernias. Finally, NE rupture inhibition could be rescued in cells treated with actin-depolymerizing drugs by mechanically constraining nucleus height. These data suggest a model of NE rupture where weak membrane areas, caused by defects in lamina organization, rupture because of an increase in intranuclear pressure from actin-based nucleus confinement.

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Silencing of Euchromatic Transposable Elements as a Consequence of Nuclear Lamina Dysfunction

Cells ◽

10.3390/cells9030625 ◽

2020 ◽

Vol 9 (3) ◽

pp. 625

Author(s):

Valeria Cavaliere ◽

Giovanna Lattanzi ◽

Davide Andrenacci

Keyword(s):

Transposable Elements ◽

Genome Instability ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

Rna Degradation ◽

Loss Of Function ◽

Heterochromatin Formation ◽

Repressive Effect ◽

Regulatory Effects ◽

Genomic Regions

Transposable elements (TEs) are mobile genomic sequences that are normally repressed to avoid proliferation and genome instability. Gene silencing mechanisms repress TEs by RNA degradation or heterochromatin formation. Heterochromatin maintenance is therefore important to keep TEs silent. Loss of heterochromatic domains has been linked to lamin mutations, which have also been associated with derepression of TEs. In fact, lamins are structural components of the nuclear lamina (NL), which is considered a pivotal structure in the maintenance of heterochromatin domains at the nuclear periphery in a silent state. Here, we show that a lethal phenotype associated with Lamin loss-of-function mutations is influenced by Drosophila gypsy retrotransposons located in euchromatic regions, suggesting that NL dysfunction has also effects on active TEs located in euchromatic loci. In fact, expression analysis of different long terminal repeat (LTR) retrotransposons and of one non-LTR retrotransposon located near active genes shows that Lamin inactivation determines the silencing of euchromatic TEs. Furthermore, we show that the silencing effect on euchromatic TEs spreads to the neighboring genomic regions, with a repressive effect on nearby genes. We propose that NL dysfunction may have opposed regulatory effects on TEs that depend on their localization in active or repressed regions of the genome.

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Bypassing Border Control: Nuclear Envelope Rupture in Disease

Physiology ◽

10.1152/physiol.00029.2017 ◽

2018 ◽

Vol 33 (1) ◽

pp. 39-49 ◽

Cited By ~ 7

Author(s):

Gaëlle Houthaeve ◽

Joke Robijns ◽

Kevin Braeckmans ◽

Winnok H. De Vos

Keyword(s):

Dna Damage ◽

Nuclear Envelope ◽

Cancer Cells ◽

Genome Instability ◽

Pathogenic Mechanism ◽

Border Control ◽

Cellular Homeostasis ◽

Cytoplasmic Material

Recent observations in laminopathy patient cells and cancer cells have revealed that the nuclear envelope (NE) can transiently rupture during interphase. NE rupture leads to an uncoordinated exchange of nuclear and cytoplasmic material, thereby deregulating cellular homeostasis. Moreover, concurrently inflicted DNA damage could prime rupture-prone cells for genome instability. Thus, NE rupture may represent a novel pathogenic mechanism that has far-reaching consequences for cell and organism physiology.

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Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains

10.1101/2020.11.17.386797 ◽

2020 ◽

Author(s):

Cristiana Bersaglieri ◽

Jelena Kresoja-Rakic ◽

Shivani Gupta ◽

Dominik Bär ◽

Rostyslav Kuzyakiv ◽

...

Keyword(s):

Nuclear Periphery ◽

Interaction Strength ◽

Nuclear Lamina ◽

Nuclear Space ◽

Chromosome Architecture ◽

Neural Genes ◽

Repressive Chromatin ◽

Genome Wide ◽

Nuclear Environment

AbstractEukaryotic chromosomes are folded into hierarchical domains, enabling the organization of the genome into functional compartments. Nuclear periphery and nucleolus are two nuclear landmarks thought to contribute to repressive chromosome architecture. However, while the role of nuclear lamina (NL) in genome organization has been well documented, the function of the nucleolus remains under-investigated due to the lack of methods for genome-wide maps of nucleolar associated domains (NADs). Here we established a method based on a Dam-fused engineered nucleolar histone H2B that marks DNA contacting the nucleolus. NAD-maps of ESCs and neural progenitors revealed layers of genome compartmentalization with distinct, repressive chromatin states based on the interaction with the nucleolus, NL, or both. NADs showed higher H3K9me2 and lower H3K27me3 content than regions exclusively interacting with NL. Upon ESC differentiation, chromosomes around the nucleolus acquire a more compact, rigid architecture whereas NADs specific for ESCs decrease their interaction strength within the repressive B-compartment strength, unlocking neural genes from repressive nuclear environment. The methodologies here developed will make possible to include the contribution of the nucleolus in future studies investigating the relationship between nuclear space and genome function.

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Relationships at the nuclear envelope: lamins and nuclear pore complexes in animals and plants

Biochemical Society Transactions ◽

10.1042/bst0380829 ◽

2010 ◽

Vol 38 (3) ◽

pp. 829-831 ◽

Cited By ~ 31

Author(s):

Jindriska Fiserova ◽

Martin W. Goldberg

Keyword(s):

Nuclear Envelope ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Nucleocytoplasmic Trafficking ◽

Animal Cells ◽

Cellular Processes ◽

Associated Proteins ◽

Pore Complexes

The nuclear envelope comprises a distinct compartment at the nuclear periphery that provides a platform for communication between the nucleus and cytoplasm. Signal transfer can proceed by multiple means. Primarily, this is by nucleocytoplasmic trafficking facilitated by NPCs (nuclear pore complexes). Recently, it has been indicated that signals can be transmitted from the cytoskeleton to the intranuclear structures via interlinking transmembrane proteins. In animal cells, the nuclear lamina tightly underlies the inner nuclear membrane and thus represents the protein structure located at the furthest boundary of the nucleus. It enables communication between the nucleus and the cytoplasm via its interactions with chromatin-binding proteins, transmembrane and membrane-associated proteins. Of particular interest is the interaction of the nuclear lamina with NPCs. As both structures fulfil essential roles in close proximity at the nuclear periphery, their interactions have a large impact on cellular processes resulting in affects on tissue differentiation and development. The present review concentrates on the structural and functional lamina–NPC relationship in animal cells and its potential implications to plants.

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Nuclear lamina and regulation of nuclear envelofe structure

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128328 ◽

1987 ◽

Vol 45 ◽

pp. 806-807

Author(s):

Larry Gerace ◽

Ueli Aebi ◽

Brian Burke ◽

Frank Suprynowicz

Keyword(s):

Electron Microscopy ◽

Nuclear Envelope ◽

Xenopus Oocytes ◽

Nuclear Periphery ◽

Nuclear Architecture ◽

Supramolecular Assembly ◽

Nuclear Lamina ◽

Eukaryotic Cells ◽

Functional Studies ◽

Tetragonal Lattice

The nuclear lamina is a protein meshwork that lines the nucleoplasmic surface of the nuclear envelope. In numerous higher eukaryotic cells, the lamina is known to contain a polymer of 1-3 major polypeptides (“lamins“) that form an insoluble supramolecular assembly during interphase. The lamina is thought to provide both a skeletal framework for the nuclear envelope (that regulates its disassembly and reformation during mitosis) and an anchoring site at the nuclear periphery for interphase chromosomes. Recent structural and functional studies on the nuclear lamina have yielded important new insight on its roles in nuclear architecture.Using electron microscopy, we found that the nuclear lamina of Xenopus oocytes is a meshwork of intermediate-sized (8-12 nm) filaments arranged in a near-tetragonal lattice having a spacing of 52 nm.

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Time-resolved, in vivo studies of mitotic spindle formation and nuclear lamina breakdown in Drosophila early embryos

Journal of Cell Science ◽

10.1242/jcs.109.3.591 ◽

1996 ◽

Vol 109 (3) ◽

pp. 591-607 ◽

Cited By ~ 10

Author(s):

M.R. Paddy ◽

H. Saumweber ◽

D.A. Agard ◽

J.W. Sedat

Keyword(s):

Nuclear Envelope ◽

Mitotic Spindle ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

In Vivo Studies ◽

Time Interval ◽

Microscopy Imaging ◽

Spindle Formation ◽

Time Resolved ◽

Early Embryos

Time-resolved, two-component, three-dimensional fluorescence light microscopy imaging in living Drosophila early embryos is used to demonstrate that a large fraction of the nuclear envelope lamins remain localized to a rim in the nuclear periphery until well into metaphase. The process of lamin delocalization and dispersal, typical of ‘open’ forms of mitosis, does not begin until about the time the final, metaphase geometry of the mitotic spindle is attained. Lamin dispersal is completed about the time that the chromosomal movements of anaphase begin. This pattern of nuclear lamina breakdown appears to be intermediate between traditional designations of ‘open’ and ‘closed’ mitoses. These results thus clarify earlier observations of lamins in mitosis in fixed Drosophila early embryos, clearly showing that the observed lamin localization does not result from a structurally defined ‘spindle envelope’ that persists throughout mitosis. During this extended time interval of lamin localization in the nuclear periphery, the lamina undergoes an extensive series of structural rearrangements that are closely coupled to, and likely driven by, the movements of the centrosomes and microtubules that produce the mitotic spindle. Furthermore, throughout this time the nuclear envelope structure is permeable to large macromolecules, which are excluded in interphase. While the functional significance of these structural dynamics is not yet clear, it is consistent with a functional role for the lamina in mitotic spindle formation.

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Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms

Epigenetics & Chromatin ◽

10.1186/s13072-021-00434-3 ◽

2022 ◽

Vol 15 (1) ◽

Author(s):

Ya-Hui Chi ◽

Wan-Ping Wang ◽

Ming-Chun Hung ◽

Gunn-Guang Liou ◽

Jing-Ya Wang ◽

...

Keyword(s):

Nuclear Envelope ◽

Cell Lines ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

Lamin A ◽

Nuclear Deformation ◽

Smad Signaling ◽

Lamin B1 ◽

Compositional Changes ◽

Nucleosomal Structure

AbstractThe cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFβ1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, clustering at the nuclear periphery and reintegrating into the nucleoplasm. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFβ1-induced compositional changes in the chromatin and nuclear lamina.

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Deformation of the nucleus by TGFβ1 via the remodeling of nuclear envelope and histone isoforms

10.21203/rs.3.rs-702270/v1 ◽

2021 ◽

Author(s):

Ya-Hui Chi ◽

Wan-Ping Wang ◽

Ming-Chun Hung ◽

Gunn-Guang Liou ◽

Jing-Ya Wang ◽

...

Keyword(s):

Nuclear Envelope ◽

Dna Damage Response ◽

Nuclear Periphery ◽

Nuclear Lamina ◽

Lamin A ◽

Nuclear Deformation ◽

Lamin B1 ◽

Damage Response ◽

Compositional Changes ◽

Nucleosomal Structure

Abstract The cause of nuclear shape abnormalities which are often seen in pre-neoplastic and malignant tissues is not clear. In this study we report that deformation of the nucleus can be induced by TGFβ1 stimulation in several cell lines including Huh7. In our results, the upregulated histone H3.3 expression downstream of SMAD signaling contributed to TGFβ1-induced nuclear deformation, a process of which requires incorporation of the nuclear envelope (NE) proteins lamin B1 and SUN1. During this process, the NE constitutively ruptured and reformed with no observable indications of DNA damage response. Contrast to lamin B1 which was relatively stationary around the nucleus, the upregulated lamin A was highly mobile, shuttling between the nucleus and cytoplasm, and clustering at the nuclear periphery. The chromatin regions that lost NE coverage formed a supra-nucleosomal structure characterized by elevated histone H3K27me3 and histone H1, the formation of which depended on the presence of lamin A. These results provide evidence that shape of the nucleus can be modulated through TGFβ1-induced compositional changes in the chromatin and nuclear lamina.

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