Closing the (nuclear) envelope on the genome: How nuclear lamins interact with promoters and modulate gene expression

The eukaryotic nucleus controls most cellular processes. It is isolated from the cytoplasm by the nuclear envelope, which plays a prominent role in the structural organization of the cell, including nucleocytoplasmic communication, chromatin positioning, and gene expression. Alterations in nuclear composition and function are eminently pronounced upon stress and during premature and physiological aging. These alterations are often accompanied by epigenetic changes in histone modifications. We review, here, the role of nuclear envelope proteins and histone modifiers in the 3-dimensional organization of the genome and the implications for gene expression. In particular, we focus on the nuclear lamins and the chromatin-associated protein BAF, which are linked to Hutchinson–Gilford and Nestor–Guillermo progeria syndromes, respectively. We also discuss alterations in nuclear organization and the epigenetic landscapes during normal aging and various stress conditions, ranging from yeast to humans.

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What Are the Potential Roles of Nuclear Perlecan and Other Heparan Sulphate Proteoglycans in the Normal and Malignant Phenotype

International Journal of Molecular Sciences ◽

10.3390/ijms22094415 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4415

Author(s):

Anthony J. Hayes ◽

James Melrose

Keyword(s):

Gene Expression ◽

Nuclear Envelope ◽

Annulus Fibrosus ◽

Heparan Sulphate ◽

Cell Types ◽

Malignant Cell ◽

Cytoskeletal Proteins ◽

Nucleus Pulposus Cells ◽

Malignant Phenotype ◽

Heparan Sulphate Proteoglycans

The recent discovery of nuclear and perinuclear perlecan in annulus fibrosus and nucleus pulposus cells and its known matrix stabilizing properties in tissues introduces the possibility that perlecan may also have intracellular stabilizing or regulatory roles through interactions with nuclear envelope or cytoskeletal proteins or roles in nucleosomal-chromatin organization that may regulate transcriptional factors and modulate gene expression. The nucleus is a mechano-sensor organelle, and sophisticated dynamic mechanoresponsive cytoskeletal and nuclear envelope components support and protect the nucleus, allowing it to perceive and respond to mechano-stimulation. This review speculates on the potential roles of perlecan in the nucleus based on what is already known about nuclear heparan sulphate proteoglycans. Perlecan is frequently found in the nuclei of tumour cells; however, its specific role in these diseased tissues is largely unknown. The aim of this review is to highlight probable roles for this intriguing interactive regulatory proteoglycan in the nucleus of normal and malignant cell types.

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Supramolecular Structures of the Dictyostelium Lamin NE81

Cells ◽

10.3390/cells8020162 ◽

2019 ◽

Vol 8 (2) ◽

pp. 162

Author(s):

Marianne Grafe ◽

Petros Batsios ◽

Irene Meyer ◽

Daria Lisin ◽

Otto Baumann ◽

...

Keyword(s):

Electron Microscopy ◽

Nuclear Envelope ◽

Model Organism ◽

Super Resolution ◽

Nuclear Lamina ◽

Stimulated Emission ◽

Structural Level ◽

Animal Cells ◽

Nuclear Lamins

Nuclear lamins are nucleus-specific intermediate filaments (IF) found at the inner nuclear membrane (INM) of the nuclear envelope (NE). Together with nuclear envelope transmembrane proteins, they form the nuclear lamina and are crucial for gene regulation and mechanical robustness of the nucleus and the whole cell. Recently, we characterized Dictyostelium NE81 as an evolutionarily conserved lamin-like protein, both on the sequence and functional level. Here, we show on the structural level that the Dictyostelium NE81 is also capable of assembling into filaments, just as metazoan lamin filament assemblies. Using field-emission scanning electron microscopy, we show that NE81 expressed in Xenopous oocytes forms filamentous structures with an overall appearance highly reminiscent of Xenopus lamin B2. The in vitro assembly properties of recombinant His-tagged NE81 purified from Dictyostelium extracts are very similar to those of metazoan lamins. Super-resolution stimulated emission depletion (STED) and expansion microscopy (ExM), as well as transmission electron microscopy of negatively stained purified NE81, demonstrated its capability of forming filamentous structures under low-ionic-strength conditions. These results recommend Dictyostelium as a non-mammalian model organism with a well-characterized nuclear envelope involving all relevant protein components known in animal cells.

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Phosphorylation-dependent mitotic SUMOylation drives nuclear envelope–chromatin interactions

The Journal of Cell Biology ◽

10.1083/jcb.202103036 ◽

2021 ◽

Vol 220 (12) ◽

Cited By ~ 1

Author(s):

Christopher Ptak ◽

Natasha O. Saik ◽

Ashwini Premashankar ◽

Diego L. Lapetina ◽

John D. Aitchison ◽

...

Keyword(s):

Gene Expression ◽

Nuclear Envelope ◽

Spatial Organization ◽

G1 Phase ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Chromatin Binding ◽

Chromatin Interactions ◽

Sumo Ligase ◽

Pore Complexes

In eukaryotes, chromatin binding to the inner nuclear membrane (INM) and nuclear pore complexes (NPCs) contributes to spatial organization of the genome and epigenetic programs important for gene expression. In mitosis, chromatin–nuclear envelope (NE) interactions are lost and then formed again as sister chromosomes segregate to postmitotic nuclei. Investigating these processes in S. cerevisiae, we identified temporally and spatially controlled phosphorylation-dependent SUMOylation events that positively regulate postmetaphase chromatin association with the NE. Our work establishes a phosphorylation-mediated targeting mechanism of the SUMO ligase Siz2 to the INM during mitosis, where Siz2 binds to and SUMOylates the VAP protein Scs2. The recruitment of Siz2 through Scs2 is further responsible for a wave of SUMOylation along the INM that supports the assembly and anchorage of subtelomeric chromatin at the INM and localization of an active gene (INO1) to NPCs during the later stages of mitosis and into G1-phase.

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Nuclear envelope localization of human UNC84A does not require nuclear lamins

FEBS Letters ◽

10.1016/j.febslet.2006.01.039 ◽

2006 ◽

Vol 580 (5) ◽

pp. 1263-1268 ◽

Cited By ~ 51

Author(s):

Sameez Hasan ◽

Stephan Güttinger ◽

Petra Mühlhäusser ◽

Fabian Anderegg ◽

Simone Bürgler ◽

...

Keyword(s):

Nuclear Envelope ◽

Nuclear Lamins

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The expression, lamin-dependent localization and RNAi depletion phenotype for emerin inC. elegans

Journal of Cell Science ◽

10.1242/jcs.115.5.923 ◽

2002 ◽

Vol 115 (5) ◽

pp. 923-929 ◽

Cited By ~ 4

Author(s):

Yosef Gruenbaum ◽

Kenneth K. Lee ◽

Jun Liu ◽

Merav Cohen ◽

Katherine L. Wilson

Keyword(s):

Nuclear Envelope ◽

Molecular Mechanisms ◽

Cell Types ◽

Growth Conditions ◽

Rnai Phenotype ◽

Lamin B ◽

C Elegans ◽

Nuclear Lamins ◽

First Time

Emerin belongs to the LEM-domain family of nuclear membrane proteins, which are conserved in metazoans from C. elegans to humans. Loss of emerin in humans causes the X-linked form of Emery-Dreifuss muscular dystrophy(EDMD), but the disease mechanism is not understood. We have begun to address the function of emerin in C. elegans, a genetically tractable nematode. The emerin gene (emr-1) is conserved in C. elegans. We detect Ce-emerin protein in the nuclear envelopes of all cell types except sperm, and find that Ce-emerin co-immunoprecipitates with Ce-lamin from embryo lysates. We show for the first time in any organism that nuclear lamins are essential for the nuclear envelope localization of emerin during early development. We further show that four other types of nuclear envelope proteins, including fellow LEM-domain protein Ce-MAN1, as well as Ce-lamin, UNC-84 and nucleoporins do not depend on Ce-emerin for their localization. This result suggests that emerin is not essential to organize or localize the only lamin (B-type) expressed in C. elegans. We also analyzed the RNAi phenotype resulting from the loss of emerin function in C. elegans under laboratory growth conditions, and found no detectable phenotype throughout development. We propose that C. elegans is an appropriate system in which to study the molecular mechanisms of emerin function in vivo.

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Novel biochemical and functional insights into nuclear Ca2+ transport through IP3Rs and RyRs in osteoblasts

AJP Renal Physiology ◽

10.1152/ajprenal.2000.278.5.f784 ◽

2000 ◽

Vol 278 (5) ◽

pp. F784-F791 ◽

Cited By ~ 21

Author(s):

Olugbenga A. Adebanjo ◽

Gopa Biswas ◽

Baljit S. Moonga ◽

Hindupur K. Anandatheerthavarada ◽

Li Sun ◽

...

Keyword(s):

Gene Expression ◽

Nuclear Envelope ◽

Nuclear Membrane ◽

Ryanodine Receptors ◽

Functional Characterization ◽

Inositol Trisphosphate Receptors ◽

Nuclear Membranes ◽

Sds Page ◽

Direct Regulation

We report the first biochemical and functional characterization of inositol trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs) in the nuclear membrane of bone-forming (MC3T3-E1) osteoblasts. Intact nuclei fluoresced intensely with anti-RyR (Ab34) and anti-IP3R (Ab40) antisera in a typically peripheral nuclear membrane pattern. Isolated nuclear membranes were next subjected to SDS-PAGE and blotted with isoform-specific anti-receptor antisera, notably Ab40, anti-RyR-1, anti-RyR-2 (Ab129), and anti-RyR-3 (Ab180). Only anti-RyR-1 and Ab40 showed bands corresponding, respectively, to full-length RyR-1 (∼500 kDa) and IP3R-1 (∼250 kDa). Band intensity was reduced by just ∼20% after brief tryptic proteolysis of intact nuclei; this confirmed that isolated nuclear membranes were mostly free of endoplasmic reticular contaminants. Finally, the nucleoplasmic Ca2+ concentration ([Ca2+]np) was measured in single nuclei by using fura-dextran. The nuclear envelope was initially loaded with Ca2+ via Ca2+-ATPase activation (1 mM ATP and ∼100 nM Ca2+). Adequate Ca2+ loading was next confirmed by imaging the nuclear envelope (and nucleoplasm). Exposure of Ca2+-loaded nuclei to IP3 or cADP ribose resulted in a rapid and sustained [Ca2+]np elevation. Taken together, the results provide complementary evidence for nucleoplasmic Ca2+ influx in osteoblasts through nuclear membrane-resident IP3Rs and RyRs. Our findings may conceivably explain the direct regulation of osteoblastic gene expression by hormones that use the IP3-Ca2+pathway.

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Nuclear Envelope and Nuclear Pore Complexes in Neurodegenerative Diseases—New Perspectives for Therapeutic Interventions

Molecular Neurobiology ◽

10.1007/s12035-020-02168-x ◽

2020 ◽

Author(s):

Naomi Hachiya ◽

Marta Sochocka ◽

Anna Brzecka ◽

Takuto Shimizu ◽

Kazimierz Gąsiorowski ◽

...

Keyword(s):

Gene Expression ◽

Neurodegenerative Diseases ◽

Nuclear Envelope ◽

Neurodegenerative Disorders ◽

Nuclear Transport ◽

Therapeutic Interventions ◽

Nuclear Pore ◽

Nuclear Pore Complexes ◽

Pore Complexes ◽

Bidirectional Exchange

Abstract Transport of proteins, transcription factors, and other signaling molecules between the nucleus and cytoplasm is necessary for signal transduction. The study of these transport phenomena is particularly challenging in neurons because of their highly polarized structure. The bidirectional exchange of molecular cargoes across the nuclear envelope (NE) occurs through nuclear pore complexes (NPCs), which are aqueous channels embedded in the nuclear envelope. The NE and NPCs regulate nuclear transport but are also emerging as relevant regulators of chromatin organization and gene expression. The alterations in nuclear transport are regularly identified in affected neurons associated with human neurodegenerative diseases. This review presents insights into the roles played by nuclear transport defects in neurodegenerative disease, focusing primarily on NE proteins and NPCs. The subcellular mislocalization of proteins might be a very desirable means of therapeutic intervention in neurodegenerative disorders.

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Integral Membrane Proteins of the Nuclear Envelope Are Dispersed throughout the Endoplasmic Reticulum during Mitosis

The Journal of Cell Biology ◽

10.1083/jcb.137.6.1199 ◽

1997 ◽

Vol 137 (6) ◽

pp. 1199-1210 ◽

Cited By ~ 160

Author(s):

Li Yang ◽

Tinglu Guan ◽

Larry Gerace

Keyword(s):

Membrane Proteins ◽

Nuclear Envelope ◽

Nuclear Membrane ◽

Mammalian Cells ◽

Polyclonal Antibodies ◽

Integral Membrane Proteins ◽

Immunogold Electron Microscopy ◽

Nuclear Pore ◽

Nuclear Lamins ◽

Nuclear Membranes

We have analyzed the fate of several integral membrane proteins of the nuclear envelope during mitosis in cultured mammalian cells to determine whether nuclear membrane proteins are present in a vesicle population distinct from bulk ER membranes after mitotic nuclear envelope disassembly or are dispersed throughout the ER. Using immunofluorescence staining and confocal microscopy, we compared the localization of two inner nuclear membrane proteins (laminaassociated polypeptides 1 and 2 [LAP1 and LAP2]) and a nuclear pore membrane protein (gp210) to the distribution of bulk ER membranes, which was determined with lipid dyes (DiOC6 and R6) and polyclonal antibodies. We found that at the resolution of this technique, the three nuclear envelope markers become completely dispersed throughout ER membranes during mitosis. In agreement with these results, we detected LAP1 in most membranes containing ER markers by immunogold electron microscopy of metaphase cells. Together, these findings indicate that nuclear membranes lose their identity as a subcompartment of the ER during mitosis. We found that nuclear lamins begin to reassemble around chromosomes at the end of mitosis at the same time as LAP1 and LAP2 and propose that reassembly of the nuclear envelope at the end of mitosis involves sorting of integral membrane proteins to chromosome surfaces by binding interactions with lamins and chromatin.

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