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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Nuclei: Function, Transport and Receptors".

Deadline for manuscript submissions: closed (15 September 2019) | Viewed by 85299

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Dr. Peter Askjaer

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Guest Editor

Andalusian Center for Developmental Biology (CABD), Spanish Research Council, Universidad Pablo de Olavide, Sevilla, Spain
Interests: nuclear envelope; nuclear pore complex; laminopathies; aging; nuclear organization; chromatin structure and function; gene regulation; chromosome segregation; nucleocytoplasmic transport; live microscopy
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Dear Colleagues,

The nucleus is a fascinating organelle of eukaryotic cells. It contains and organises the chromosomes, which implies that many biological processes depend on nuclear organisation, as well as regulated communication between the nucleus and its surrounding organelles and cytoplasm. The aim of this Special Issue of Cells is to provide a comprehensive overview of our current knowledge about the nucleus, spanning from the structure and function of the nuclear envelope to the three-dimensional organisation of chromosomes in territories and domains. Both fundamental aspects of cell biology and mechanisms to ensure and utilise cell type-specific nuclear organisation will be addressed by specialists that exploit a wide variety of genetical, biochemical, and genomics methods across different organisms.

Nuclear organisation is also highly relevant from a biomedical viewpoint. Since the discovery that mutations in nuclear envelope proteins cause a pleiotropy of severe human diseases, including muscular dystrophies, bone disorders, neuropathies, and even premature ageing, many efforts have been devoted to understanding the protective, scaffolding, and regulatory roles of the nuclear envelope. Modern advances in genomics have revealed that perturbations in the discrete folding of chromatin in topologically associating domains can also have profound effects during development. Most recently, multidisciplinary approaches have begun to unravel the principles underlying the segregation of heterochromatin from euchromatin—a separation that was already appreciated in early microscopy studies but is now better understood by employing epigenetics and biophysical tools. By integrating up-to-date insight from these different areas, we are in an unprecedented position to recognise the dynamics and implications of the incredible complexity found within our nuclei.

Dr. Peter Askjaer
Guest Editor

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Keywords

Nuclear Envelope
Chromatin Organisation
Topologically Associating Domain
Gene Expression
Phase Separation

Related Special Issues

Regulation of Nuclear Organization and Function in Cells (6 articles)
Heterochromatin Formation and Function in Cells (10 articles)

Published Papers (12 papers)

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Research

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16 pages, 2270 KiB

Open AccessArticle

Mitotic Chromosomes in Live Cells Characterized Using High-Speed and Label-Free Optical Diffraction Tomography

by Tae-Keun Kim, Byong-Wook Lee, Fumihiko Fujii, Kee-Hang Lee, Sanghwa Lee, YongKeun Park, Jun Ki Kim, Sang-Wook Lee and Chan-Gi Pack

Cells 2019, 8(11), 1368; https://doi.org/10.3390/cells8111368 - 31 Oct 2019

Cited by 19 | Viewed by 6976

Abstract

The cell nucleus is a three-dimensional, dynamic organelle organized into subnuclear compartments such as chromatin and nucleoli. The structure and function of these compartments are maintained by diffusion and interactions between related factors as well as by dynamic and structural changes. Recent studies using fluorescent microscopic techniques suggest that protein factors can access and are freely mobile in heterochromatin and in mitotic chromosomes, despite their densely packed structure. However, the physicochemical properties of the chromosome during cell division are not fully understood. In the present study, characteristic properties such as the refractive index (RI), volume of the mitotic chromosomes, and diffusion coefficient (D) of fluorescent probes inside the chromosome were quantified using an approach combining label-free optical diffraction tomography with complementary confocal laser-scanning microscopy and fluorescence correlation spectroscopy. Variations in these parameters correlated with osmotic conditions, suggesting that changes in RI are consistent with those of the diffusion coefficient for mitotic chromosomes and cytosol. Serial RI tomography images of chromosomes in live cells during mitosis were compared with three-dimensional confocal micrographs to demonstrate that compaction and decompaction of chromosomes induced by osmotic change were characterized by linked changes in chromosome RI, volume, and the mobilities of fluorescent proteins. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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13 pages, 14456 KiB

Open AccessArticle

Triple-Helical DNA in Drosophila Heterochromatin

by Eduardo Gorab

Cells 2018, 7(12), 227; https://doi.org/10.3390/cells7120227 - 23 Nov 2018

Cited by 3 | Viewed by 4098

Abstract

Polynucleotide chains obeying Watson-Crick pairing are apt to form non-canonical complexes such as triple-helical nucleic acids. From early characterization in vitro, their occurrence in vivo has been strengthened by increasing evidence, although most remain circumstantial particularly for triplex DNA. Here, different approaches were employed to specify triple-stranded DNA sequences in the Drosophila melanogaster chromosomes. Antibodies to triplex nucleic acids, previously characterized, bind to centromeric regions of mitotic chromosomes and also to the polytene section 59E of mutant strains carrying the brown dominant allele, indicating that AAGAG tandem satellite repeats are triplex-forming sequences. The satellite probe hybridized to AAGAG-containing regions omitting chromosomal DNA denaturation, as expected, for the intra-molecular triplex DNA formation model in which single-stranded DNA coexists with triplexes. In addition, Thiazole Orange, previously described as capable of reproducing results obtained by antibodies to triple-helical DNA, binds to AAGAG repeats in situ thus validating both detection methods. Unusual phenotype and nuclear structure exhibited by Drosophila correlate with the non-canonical conformation of tandem satellite arrays. From the approaches that lead to the identification of triple-helical DNA in chromosomes, facilities particularly provided by Thiazole Orange use may broaden the investigation on the occurrence of triplex DNA in eukaryotic genomes. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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Review

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17 pages, 1060 KiB

Open AccessFeature PaperReview

Metabolic Dysfunction in Hutchinson–Gilford Progeria Syndrome

by Ray Kreienkamp and Susana Gonzalo

Cells 2020, 9(2), 395; https://doi.org/10.3390/cells9020395 - 08 Feb 2020

Cited by 21 | Viewed by 11630

Abstract

Hutchinson–Gilford Progeria Syndrome (HGPS) is a segmental premature aging disease causing patient death by early teenage years from cardiovascular dysfunction. Although HGPS does not totally recapitulate normal aging, it does harbor many similarities to the normal aging process, with patients also developing cardiovascular disease, alopecia, bone and joint abnormalities, and adipose changes. It is unsurprising, then, that as physicians and scientists have searched for treatments for HGPS, they have targeted many pathways known to be involved in normal aging, including inflammation, DNA damage, epigenetic changes, and stem cell exhaustion. Although less studied at a mechanistic level, severe metabolic problems are observed in HGPS patients. Interestingly, new research in animal models of HGPS has demonstrated impressive lifespan improvements secondary to metabolic interventions. As such, further understanding metabolism, its contribution to HGPS, and its therapeutic potential has far-reaching ramifications for this disease still lacking a robust treatment strategy. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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18 pages, 1027 KiB

Open AccessFeature PaperReview

Nuclear Pore Proteins in Regulation of Chromatin State

by Terra M. Kuhn and Maya Capelson

Cells 2019, 8(11), 1414; https://doi.org/10.3390/cells8111414 - 09 Nov 2019

Cited by 33 | Viewed by 5834

Abstract

Nuclear pore complexes (NPCs) are canonically known to regulate nucleocytoplasmic transport. However, research efforts over the last decade have demonstrated that NPCs and their constituent nucleoporins (Nups) also interact with the genome and perform important roles in regulation of gene expression. It has become increasingly clear that many Nups execute these roles specifically through regulation of chromatin state, whether through interactions with histone modifiers and downstream changes in post-translational histone modifications, or through relationships with chromatin-remodeling proteins that can result in physical changes in nucleosome occupancy and chromatin compaction. This review focuses on these findings, highlighting the functional connection between NPCs/Nups and regulation of chromatin structure, and how this connection can manifest in regulation of transcription. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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14 pages, 1399 KiB

Open AccessReview

Nuclear Mechanics in the Fission Yeast

by Paola Gallardo, Ramón R. Barrales, Rafael R. Daga and Silvia Salas-Pino

Cells 2019, 8(10), 1285; https://doi.org/10.3390/cells8101285 - 20 Oct 2019

Cited by 6 | Viewed by 5000

Abstract

In eukaryotic cells, the organization of the genome within the nucleus requires the nuclear envelope (NE) and its associated proteins. The nucleus is subjected to mechanical forces produced by the cytoskeleton. The physical properties of the NE and the linkage of chromatin in compacted conformation at sites of cytoskeleton contacts seem to be key for withstanding nuclear mechanical stress. Mechanical perturbations of the nucleus normally occur during nuclear positioning and migration. In addition, cell contraction or expansion occurring for instance during cell migration or upon changes in osmotic conditions also result innuclear mechanical stress. Recent studies in Schizosaccharomyces pombe (fission yeast) have revealed unexpected functions of cytoplasmic microtubules in nuclear architecture and chromosome behavior, and have pointed to NE-chromatin tethers as protective elements during nuclear mechanics. Here, we review and discuss how fission yeast cells can be used to understand principles underlying the dynamic interplay between genome organization and function and the effect of forces applied to the nucleus by the microtubule cytoskeleton. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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19 pages, 1934 KiB

Open AccessReview

Enhancer Dysfunction in 3D Genome and Disease

by Ji-Han Xia and Gong-Hong Wei

Cells 2019, 8(10), 1281; https://doi.org/10.3390/cells8101281 - 19 Oct 2019

Cited by 13 | Viewed by 8301

Abstract

Spatiotemporal patterns of gene expression depend on enhancer elements and other factors during individual development and disease progression. The rapid progress of high-throughput techniques has led to well-defined enhancer chromatin properties. Various genome-wide methods have revealed a large number of enhancers and the discovery of three-dimensional (3D) genome architecture showing the distant interacting mechanisms of enhancers that loop to target gene promoters. Whole genome sequencing projects directed at cancer have led to the discovery of substantial enhancer dysfunction in misregulating gene expression and in tumor initiation and progression. Results from genome-wide association studies (GWAS) combined with functional genomics analyses have elucidated the functional impacts of many cancer risk-associated variants that are enriched within the enhancer regions of chromatin. Risk variants dysregulate the expression of enhancer variant-associated genes via 3D genomic interactions. Moreover, these enhancer variants often alter the chromatin binding affinity for cancer-relevant transcription factors, which in turn leads to aberrant expression of the genes associated with cancer susceptibility. In this review, we investigate the extent to which these genetic regulatory circuits affect cancer predisposition and how the recent development of genome-editing methods have enabled the determination of the impacts of genomic variation and alteration on cancer phenotype, which will eventually lead to better management plans and treatment responses to human cancer in the clinic. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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15 pages, 3218 KiB

Open AccessReview

The Dynamic 3D Genome in Gametogenesis and Early Embryonic Development

by Feifei Li, Ziyang An and Zhihua Zhang

Cells 2019, 8(8), 788; https://doi.org/10.3390/cells8080788 - 29 Jul 2019

Cited by 11 | Viewed by 4875

Abstract

During gametogenesis and early embryonic development, the chromatin architecture changes dramatically, and both the transcriptomic and epigenomic landscape are comprehensively reprogrammed. Understanding these processes is the holy grail in developmental biology and a key step towards evolution. The 3D conformation of chromatin plays a central role in the organization and function of nuclei. Recently, the dynamics of chromatin structures have been profiled in many model and non-model systems, from insects to mammals, resulting in an interesting comparison. In this review, we first introduce the research methods of 3D chromatin structure with low-input material suitable for embryonic study. Then, the dynamics of 3D chromatin architectures during gametogenesis and early embryonic development is summarized and compared between species. Finally, we discuss the possible mechanisms for triggering the formation of genome 3D conformation in early development. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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21 pages, 1785 KiB

Open AccessReview

Nuclear Organization in Stress and Aging

by Raquel Romero-Bueno, Patricia de la Cruz Ruiz, Marta Artal-Sanz, Peter Askjaer and Agnieszka Dobrzynska

Cells 2019, 8(7), 664; https://doi.org/10.3390/cells8070664 - 01 Jul 2019

Cited by 26 | Viewed by 6949

Abstract

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. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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27 pages, 2144 KiB

Open AccessReview

H3K18Ac as a Marker of Cancer Progression and Potential Target of Anti-Cancer Therapy

by Marta Hałasa, Anna Wawruszak, Alicja Przybyszewska, Anna Jaruga, Małgorzata Guz, Joanna Kałafut, Andrzej Stepulak and Marek Cybulski

Cells 2019, 8(5), 485; https://doi.org/10.3390/cells8050485 - 22 May 2019

Cited by 41 | Viewed by 7964

Abstract

Acetylation and deacetylation are posttranslational modifications (PTMs) which affect the regulation of chromatin structure and its remodeling. Acetylation of histone 3 at lysine placed on position 18 (H3K18Ac) plays an important role in driving progression of many types of cancer, including breast, colon, lung, hepatocellular, pancreatic, prostate, and thyroid cancer. The aim of this review is to analyze and discuss the newest findings regarding the role of H3K18Ac and acetylation of other histones in carcinogenesis. We summarize the level of H3K18Ac in different cancer cell lines and analyze its association with patients’ outcomes, including overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS). Finally, we describe future perspectives of cancer therapeutic strategies based on H3K18 modifications. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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12 pages, 895 KiB

Open AccessFeature PaperReview

Histone Methylation and Memory of Environmental Stress

by Paola Fabrizio, Steven Garvis and Francesca Palladino

Cells 2019, 8(4), 339; https://doi.org/10.3390/cells8040339 - 10 Apr 2019

Cited by 55 | Viewed by 7197

Abstract

Cellular adaptation to environmental stress relies on a wide range of tightly controlled regulatory mechanisms, including transcription. Changes in chromatin structure and organization accompany the transcriptional response to stress, and in some cases, can impart memory of stress exposure to subsequent generations through mechanisms of epigenetic inheritance. In the budding yeast Saccharomyces cerevisiae, histone post-translational modifications, and in particular histone methylation, have been shown to confer transcriptional memory of exposure to environmental stress conditions through mitotic divisions. Recent evidence from Caenorhabditis elegans also implicates histone methylation in transgenerational inheritance of stress responses, suggesting a more widely conserved role in epigenetic memory. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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26 pages, 4187 KiB

Open AccessReview

The Modern View of B Chromosomes Under the Impact of High Scale Omics Analyses

by Syed Farhan Ahmad and Cesar Martins

Cells 2019, 8(2), 156; https://doi.org/10.3390/cells8020156 - 13 Feb 2019

Cited by 50 | Viewed by 8082

Abstract

Supernumerary B chromosomes (Bs) are extra karyotype units in addition to A chromosomes, and are found in some fungi and thousands of animals and plant species. Bs are uniquely characterized due to their non-Mendelian inheritance, and represent one of the best examples of genomic conflict. Over the last decades, their genetic composition, function and evolution have remained an unresolved query, although a few successful attempts have been made to address these phenomena. A classical concept based on cytogenetics and genetics is that Bs are selfish and abundant with DNA repeats and transposons, and in most cases, they do not carry any function. However, recently, the modern quantum development of high scale multi-omics techniques has shifted B research towards a new-born field that we call “B-omics”. We review the recent literature and add novel perspectives to the B research, discussing the role of new technologies to understand the mechanistic perspectives of the molecular evolution and function of Bs. The modern view states that B chromosomes are enriched with genes for many significant biological functions, including but not limited to the interesting set of genes related to cell cycle and chromosome structure. Furthermore, the presence of B chromosomes could favor genomic rearrangements and influence the nuclear environment affecting the function of other chromatin regions. We hypothesize that B chromosomes might play a key function in driving their transmission and maintenance inside the cell, as well as offer an extra genomic compartment for evolution. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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12 pages, 654 KiB

Open AccessReview

Signal Transduction across the Nuclear Envelope: Role of the LINC Complex in Bidirectional Signaling

by Miki Hieda

Cells 2019, 8(2), 124; https://doi.org/10.3390/cells8020124 - 04 Feb 2019

Cited by 36 | Viewed by 7055

Abstract

The primary functions of the nuclear envelope are to isolate the nucleoplasm and its contents from the cytoplasm as well as maintain the spatial and structural integrity of the nucleus. The nuclear envelope also plays a role in the transfer of various molecules and signals to and from the nucleus. To reach the nucleus, an extracellular signal must be transmitted across three biological membranes: the plasma membrane, as well as the inner and outer nuclear membranes. While signal transduction across the plasma membrane is well characterized, signal transduction across the nuclear envelope, which is essential for cellular functions such as transcriptional regulation and cell cycle progression, remains poorly understood. As a physical entity, the nuclear envelope, which contains more than 100 proteins, functions as a binding scaffold for both the cytoskeleton and the nucleoskeleton, and acts in mechanotransduction by relaying extracellular signals to the nucleus. Recent results show that the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which is a conserved molecular bridge that spans the nuclear envelope and connects the nucleoskeleton and cytoskeleton, is also capable of transmitting information bidirectionally between the nucleus and the cytoplasm. This short review discusses bidirectional signal transduction across the nuclear envelope, with a particular focus on mechanotransduction. Full article

(This article belongs to the Special Issue Nuclear Organisation)

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