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

Cells ◽  
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.

Hinfp is a guardian of the somatic genome by repressing transposable elements

2021 ◽  
Vol 118 (41) ◽  
pp. e2100839118
Author(s):  
Niraj K. Nirala ◽  
Qi Li ◽  
Prachi N. Ghule ◽  
Hsi-Ju Chen ◽  
Rui Li ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transposable Elements ◽  
Transposable Element ◽  
Cancer Progression ◽  
Genome Stability ◽  
Genome Instability ◽  
Tissue Growth ◽  
Loss Of Function ◽  
Element Mobilization ◽  
Host Genes

Germ cells possess the Piwi-interacting RNA pathway to repress transposable elements and maintain genome stability across generations. Transposable element mobilization in somatic cells does not affect future generations, but nonetheless can lead to pathological outcomes in host tissues. We show here that loss of function of the conserved zinc-finger transcription factor Hinfp causes dysregulation of many host genes and derepression of most transposable elements. There is also substantial DNA damage in somatic tissues of Drosophila after loss of Hinfp. Interference of transposable element mobilization by reverse-transcriptase inhibitors can suppress some of the DNA damage phenotypes. The key cell-autonomous target of Hinfp in this process is Histone1, which encodes linker histones essential for higher-order chromatin assembly. Transgenic expression of Hinfp or Histone1, but not Histone4 of core nucleosome, is sufficient to rescue the defects in repressing transposable elements and host genes. Loss of Hinfp enhances Ras-induced tissue growth and aging-related phenotypes. Therefore, Hinfp is a physiological regulator of Histone1-dependent silencing of most transposable elements, as well as many host genes, and serves as a venue for studying genome instability, cancer progression, neurodegeneration, and aging.

scholarly journals RNA-mediated nucleosome depletion is required for elimination of transposon-derived DNA.

2022 ◽  
Author(s):  
Aditi Singh ◽  
Xyrus X. Maurer-Alcalá ◽  
Therese Solberg ◽  
Silvan Gisler ◽  
Michael Ignarski ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Chromatin Remodeling ◽  
Dna Cleavage ◽  
Small Rnas ◽  
Heterochromatin Formation ◽  
Dna Accessibility ◽  
Dna Elimination ◽  
Nucleosome Density ◽  
Somatic Genome ◽  
Genomic Regions

Small RNAs are known to mediate silencing of transposable elements and other genomic loci, increasing nucleosome density and preventing undesirable gene expression. Post-zygotic development of the Paramecium somatic genome requires elimination of thousands of transposon remnants (IESs) and transposable elements that are scattered throughout the germline genome (Garnier et al. 2004). The elimination process is guided by Piwi-associated small RNAs and leads to precise cleavage at IES boundaries (Bouhouche et al. 2011; Furrer et al. 2017). Previous research suggests that small RNAs induce heterochromatin formation within IESs, which, in turn, is required for DNA elimination (Liu et al. 2007). Here we show that IES recognition and precise excision is facilitated by recruitment of a homolog of a chromatin remodeler ISWI, which depletes target genomic regions of nucleosomes, making the chromatin accessible for DNA cleavage. ISWI knockdown in Paramecium leads to pronounced inhibition of DNA elimination. Furthermore, nucleosome profiling indicates that ISWI is required for IES elimination in nucleosome-dense genomic regions, while other IESs do not require small RNAs or ISWI for excision. ISWI silencing notably also reduces DNA elimination precision, resulting in aberrant excision at alternative IES boundaries. In summary, we demonstrate that chromatin remodeling that increases DNA accessibility together with small RNAs are necessary for efficient and precise DNA elimination in Paramecium.

scholarly journals Prdm16-mediated H3K9 methylation controls fibro-adipogenic progenitors identity during skeletal muscle repair

2021 ◽  
Vol 7 (23) ◽  
pp. eabd9371
Author(s):  
Beatrice Biferali ◽  
Valeria Bianconi ◽  
Daniel Fernandez Perez ◽  
Sophie Pöhle Kronawitter ◽  
Fabrizia Marullo ◽  
...  
Keyword(s):  
Envelope Protein ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
H3k9 Methylation ◽  
Cell Type ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Genomic Regions

H3K9 methylation maintains cell identity orchestrating stable silencing and anchoring of alternate fate genes within the heterochromatic compartment underneath the nuclear lamina (NL). However, how cell type–specific genomic regions are specifically targeted to the NL is still elusive. Using fibro-adipogenic progenitors (FAPs) as a model, we identified Prdm16 as a nuclear envelope protein that anchors H3K9-methylated chromatin in a cell-specific manner. We show that Prdm16 mediates FAP developmental capacities by orchestrating lamina-associated domain organization and heterochromatin sequestration at the nuclear periphery. We found that Prdm16 localizes at the NL where it cooperates with the H3K9 methyltransferases G9a/GLP to mediate tethering and silencing of myogenic genes, thus repressing an alternative myogenic fate in FAPs. Genetic and pharmacological disruption of this repressive pathway confers to FAP myogenic competence, preventing fibro-adipogenic degeneration of dystrophic muscles. In summary, we reveal a druggable mechanism of heterochromatin perinuclear sequestration exploitable to reprogram FAPs in vivo.

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

2019 ◽  
Vol 47 (15) ◽  
pp. 7870-7885 ◽  
Author(s):  
Berta N Vazquez ◽  
Joshua K Thackray ◽  
Nicolas G Simonet ◽  
Sanjay Chahar ◽  
Noriko Kane-Goldsmith ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Cancer Cells ◽  
Knockout Mice ◽  
Transcriptional Repression ◽  
Genome Instability ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Functional Link ◽  
Long Interspersed Elements ◽  
Genome Wide

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.

scholarly journals Lamin C regulates genome organization after mitosis

2020 ◽  
Author(s):  
X Wong ◽  
VE Hoskins ◽  
JC Harr ◽  
M Gordon ◽  
KL Reddy
Keyword(s):  
Genome Organization ◽  
Mammalian Cells ◽  
Regulation Of Gene Expression ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Lamin A ◽  
3D Genome ◽  
Cellular Processes ◽  
Genomic Regions ◽  
In Cells

AbstractThe dynamic 3D organization of the genome is central to the regulation of gene expression and developmental progression, with its disruption being implicated in various diseases. The nuclear lamina, a proteinaceous meshwork underlying the nuclear envelope (NE), provides both structural and regulatory influences on genome organization through the tethering of large inactive genomic regions, called Lamina Associated Domains (LADs), to the nuclear periphery. Evidence suggests that the A type lamins, lamins A and C, are the predominant lamins involved in the peripheral association of LADs, with these two isotypes forming distinct networks and potentially involved in different cellular processes. Here we tested whether lamins A and C have distinct roles in genome organization by examining chromosome architecture in cells in which lamin C or lamin A are specifically down-regulated. We find that lamin C (not lamin A) is required for the 3D organization of LADs and overall chromosome organization in the cell nucleus. Striking differences in the localization of lamin A and lamin C are present as cells exit mitosis that persist through early G1. Whereas lamin A associates with the nascent NE during telophase, lamin C remains in the interior surrounding nucleoplasmic LAD clusters. Lamin C association with the NE is delayed until several hours into G1 and correlates temporally and spatially with the post-mitotic NE association of LADs. Post-mitotic LAD association with the NE, and consequently global 3D genome organization, is perturbed only in cells depleted of lamin C, and not in cells depleted of lamin A. We conclude that lamin C regulates LAD dynamics after mitosis and is a key regulator of genome organization in mammalian cells. These findings reveal an unexpectedly central role for lamin C in genome organization, including both inter-chromosomal LAD-LAD segregation and LAD scaffolding at the NE.

scholarly journals Lamin B1 acetylation slows the G1 to S cell cycle transition through inhibition of DNA repair

2021 ◽  
Author(s):  
Laura A Murray-Nerger ◽  
Joshua L Justice ◽  
Pranav Rekapalli ◽  
Josiah E Hutton ◽  
Ileana M Cristea
Keyword(s):  
Cell Cycle ◽  
Dna Repair ◽  
Posttranslational Modifications ◽  
Cell Cycle Progression ◽  
Nuclear Periphery ◽  
Virus Production ◽  
Nuclear Lamina ◽  
Regulatory Function ◽  
Herpesvirus Type ◽  
Lamin B1

Abstract The integrity and regulation of the nuclear lamina is essential for nuclear organization and chromatin stability, with its dysregulation being linked to laminopathy diseases and cancer. Although numerous posttranslational modifications have been identified on lamins, few have been ascribed a regulatory function. Here, we establish that lamin B1 (LMNB1) acetylation at K134 is a molecular toggle that controls nuclear periphery stability, cell cycle progression, and DNA repair. LMNB1 acetylation prevents lamina disruption during herpesvirus type 1 (HSV-1) infection, thereby inhibiting virus production. We also demonstrate the broad impact of this site on laminar processes in uninfected cells. LMNB1 acetylation negatively regulates canonical nonhomologous end joining by impairing the recruitment of 53BP1 to damaged DNA. This defect causes a delay in DNA damage resolution and a persistent activation of the G1/S checkpoint. Altogether, we reveal LMNB1 acetylation as a mechanism for controlling DNA repair pathway choice and stabilizing the nuclear periphery.

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

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.

scholarly journals Distinct Responses of Arabidopsis Telomeres and Transposable Elements to Zebularine Exposure

2021 ◽  
Vol 22 (1) ◽  
pp. 468
Author(s):  
Klára Konečná ◽  
Pavla Polanská Sováková ◽  
Karin Anteková ◽  
Jiří Fajkus ◽  
Miloslava Fojtová
Keyword(s):  
Transposable Elements ◽  
Transcriptional Activation ◽  
Genome Stability ◽  
Cytosine Methylation ◽  
Individual Variability ◽  
Correlated Response ◽  
Telomere Shortening ◽  
Treatment Changes ◽  
Telomere Homeostasis ◽  
Genomic Regions

Involvement of epigenetic mechanisms in the regulation of telomeres and transposable elements (TEs), genomic regions with the protective and potentially detrimental function, respectively, has been frequently studied. Here, we analyzed telomere lengths in Arabidopsis thaliana plants of Columbia, Landsberg erecta and Wassilevskija ecotypes exposed repeatedly to the hypomethylation drug zebularine during germination. Shorter telomeres were detected in plants growing from seedlings germinated in the presence of zebularine with a progression in telomeric phenotype across generations, relatively high inter-individual variability, and diverse responses among ecotypes. Interestingly, the extent of telomere shortening in zebularine Columbia and Wassilevskija plants corresponded to the transcriptional activation of TEs, suggesting a correlated response of these genomic elements to the zebularine treatment. Changes in lengths of telomeres and levels of TE transcripts in leaves were not always correlated with a hypomethylation of cytosines located in these regions, indicating a cytosine methylation-independent level of their regulation. These observations, including differences among ecotypes together with distinct dynamics of the reversal of the disruption of telomere homeostasis and TEs transcriptional activation, reflect a complex involvement of epigenetic processes in the regulation of crucial genomic regions. Our results further demonstrate the ability of plant cells to cope with these changes without a critical loss of the genome stability.

scholarly journals Nuclear Cytoskeleton in Virus Infection

2022 ◽  
Vol 23 (1) ◽  
pp. 578
Author(s):  
Lenka Horníková ◽  
Kateřina Bruštíková ◽  
Sandra Huérfano ◽  
Jitka Forstová
Keyword(s):  
Virus Infection ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
Nuclear Actin ◽  
Nuclear Egress ◽  
Viral Particles ◽  
Replication Sites ◽  
Main Component ◽  
Virus Egress ◽  
Natural Barrier

The nuclear lamina is the main component of the nuclear cytoskeleton that maintains the integrity of the nucleus. However, it represents a natural barrier for viruses replicating in the cell nucleus. The lamina blocks viruses from being trafficked to the nucleus for replication, but it also impedes the nuclear egress of the progeny of viral particles. Thus, viruses have evolved mechanisms to overcome this obstacle. Large viruses induce the assembly of multiprotein complexes that are anchored to the inner nuclear membrane. Important components of these complexes are the viral and cellular kinases phosphorylating the lamina and promoting its disaggregation, therefore allowing virus egress. Small viruses also use cellular kinases to induce lamina phosphorylation and the subsequent disruption in order to facilitate the import of viral particles during the early stages of infection or during their nuclear egress. Another component of the nuclear cytoskeleton, nuclear actin, is exploited by viruses for the intranuclear movement of their particles from the replication sites to the nuclear periphery. This study focuses on exploitation of the nuclear cytoskeleton by viruses, although this is just the beginning for many viruses, and promises to reveal the mechanisms and dynamic of physiological and pathological processes in the nucleus.

scholarly journals Emerging Technologies for Genome-Wide Profiling of DNA Breakage

2021 ◽  
Vol 11 ◽  
Author(s):  
Matthew J. Rybin ◽  
Melina Ramic ◽  
Natalie R. Ricciardi ◽  
Philipp Kapranov ◽  
Claes Wahlestedt ◽  
...  
Keyword(s):  
Genome Instability ◽  
Dna Double Strand Breaks ◽  
Single Nucleotide ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Genome Wide ◽  
A Genome ◽  
Wide Scale ◽  
Nucleotide Resolution ◽  
Genomic Regions

Genome instability is associated with myriad human diseases and is a well-known feature of both cancer and neurodegenerative disease. Until recently, the ability to assess DNA damage—the principal driver of genome instability—was limited to relatively imprecise methods or restricted to studying predefined genomic regions. Recently, new techniques for detecting DNA double strand breaks (DSBs) and single strand breaks (SSBs) with next-generation sequencing on a genome-wide scale with single nucleotide resolution have emerged. With these new tools, efforts are underway to define the “breakome” in normal aging and disease. Here, we compare the relative strengths and weaknesses of these technologies and their potential application to studying neurodegenerative diseases.

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