Review

Authors: Bas van Steensel, Andrew S Belmont

In metazoan cell nuclei, hundreds of large chromatin domains are in close contact with the nuclear lamina. Such lamina-associated domains (LADs) are thought to help organize chromosomes inside the nucleus and have been associated with gene repression. Here, we discuss the properties of LADs, the molecular mechanisms that determine their association with the nuclear lamina, their dynamic links with other nuclear compartments, and their proposed roles in gene regulation.

Topics: Animals; Cell Nucleus; Chromatin; Gene Expression Regulation; Heterochromatin; Humans; Lamins; Nuclear Lamina; Nuclear Pore

PubMed: 28525751
DOI: 10.1016/j.cell.2017.04.022

Authors: Ion Andreu, Ignasi Granero-Moya, Nimesh R Chahare...

Mechanical force controls fundamental cellular processes in health and disease, and increasing evidence shows that the nucleus both experiences and senses applied forces. Such forces can lead to the nuclear translocation of proteins, but whether force controls nucleocytoplasmic transport, and how, remains unknown. Here we show that nuclear forces differentially control passive and facilitated nucleocytoplasmic transport, setting the rules for the mechanosensitivity of shuttling proteins. We demonstrate that nuclear force increases permeability across nuclear pore complexes, with a dependence on molecular weight that is stronger for passive than for facilitated diffusion. Owing to this differential effect, force leads to the translocation of cargoes into or out of the nucleus within a given range of molecular weight and affinity for nuclear transport receptors. Further, we show that the mechanosensitivity of several transcriptional regulators can be both explained by this mechanism and engineered exogenously by introducing appropriate nuclear localization signals. Our work unveils a mechanism of mechanically induced signalling, probably operating in parallel with others, with potential applicability across signalling pathways.

Topics: Active Transport, Cell Nucleus; Cell Nucleus; Nuclear Pore; Protein Transport; Receptors, Cytoplasmic and Nuclear

PubMed: 35681009
DOI: 10.1038/s41556-022-00927-7

Authors: Sofia A Quinodoz, Noah Ollikainen, Barbara Tabak...

Eukaryotic genomes are packaged into a 3-dimensional structure in the nucleus. Current methods for studying genome-wide structure are based on proximity ligation. However, this approach can fail to detect known structures, such as interactions with nuclear bodies, because these DNA regions can be too far apart to directly ligate. Accordingly, our overall understanding of genome organization remains incomplete. Here, we develop split-pool recognition of interactions by tag extension (SPRITE), a method that enables genome-wide detection of higher-order interactions within the nucleus. Using SPRITE, we recapitulate known structures identified by proximity ligation and identify additional interactions occurring across larger distances, including two hubs of inter-chromosomal interactions that are arranged around the nucleolus and nuclear speckles. We show that a substantial fraction of the genome exhibits preferential organization relative to these nuclear bodies. Our results generate a global model whereby nuclear bodies act as inter-chromosomal hubs that shape the overall packaging of DNA in the nucleus.

Topics: Cell Nucleolus; Cell Nucleus; Chromosome Mapping; Chromosomes; DNA; Eukaryota; Genome; Humans; Structure-Activity Relationship

PubMed: 29887377
DOI: 10.1016/j.cell.2018.05.024

Review

Authors: Gregg G Gundersen, Howard J Worman

The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways.

Topics: Animals; Biomechanical Phenomena; Cell Nucleus; Cells; Cytoskeleton; Humans; Microtubules

PubMed: 23498944
DOI: 10.1016/j.cell.2013.02.031

Review

Authors: Ashley Kaminski, Gregory R Fedorchak, Jan Lammerding...

Cells respond to mechanical stimulation by activation of specific signaling pathways and genes that allow the cell to adapt to its dynamic physical environment. How cells sense the various mechanical inputs and translate them into biochemical signals remains an area of active investigation. Recent reports suggest that the cell nucleus may be directly implicated in this cellular mechanotransduction process. Taken together, these findings paint a picture of the nucleus as a central hub in cellular mechanotransduction-both structurally and biochemically-with important implications in physiology and disease.

Topics: Animals; Cell Nucleus; Cell Nucleus Structures; Disease; Humans; Mechanotransduction, Cellular

PubMed: 25081618
DOI: 10.1016/B978-0-12-394624-9.00007-5

Authors: Helmut Schiessel

Several simulation studies have recently appeared in Biophysical Journal that investigate the formation of biomolecular condensates in the nucleus. These structures explain a large variety of biological phenomena, from epigenetic inheritance, to enhancer-promoter interactions, to the spatial organization of the entire cell nucleus.

Topics: Chromatin; Computer Simulation; Cell Nucleus

PubMed: 36261037
DOI: 10.1016/j.bpj.2022.10.007

Review

Authors: Bojana Lucic, Ines J de Castro, Marina Lusic...

Viral infection is intrinsically linked to the capacity of the virus to generate progeny. Many DNA and some RNA viruses need to access the nuclear machinery and therefore transverse the nuclear envelope barrier through the nuclear pore complex. Viral genomes then become chromatinized either in their episomal form or upon integration into the host genome. Interactions with host DNA, transcription factors or nuclear bodies mediate their replication. Often interfering with nuclear functions, viruses use nuclear architecture to ensure persistent infections. Discovering these multiple modes of replication and persistence served in unraveling many important nuclear processes, such as nuclear trafficking, transcription, and splicing. Here, by using examples of DNA and RNA viral families, we portray the nucleus with the virus inside.

Topics: Animals; Cell Nucleus; DNA Viruses; Gene Expression Regulation, Viral; Humans; RNA Viruses; Virus Integration

PubMed: 33753405
DOI: 10.1101/cshperspect.a039446

Review

Authors: Malgorzata Kloc, Jarek Wosik

Individual cells and cells within the tissues and organs constantly face mechanical challenges, such as tension, compression, strain, shear stress, and the rigidity of cellular and extracellular surroundings. Besides the external mechanical forces, cells and their components are also subjected to intracellular mechanical forces, such as pulling, pushing, and stretching, created by the sophisticated force-generation machinery of the cytoskeleton and molecular motors. All these mechanical stressors switch on the mechanotransduction pathways, allowing cells and their components to respond and adapt. Mechanical force-induced changes at the cell membrane and cytoskeleton are also transmitted to the nucleus and its nucleoskeleton, affecting nucleocytoplasmic transport, chromatin conformation, transcriptional activity, replication, and genome, which, in turn, orchestrate cellular mechanical behavior. The memory of mechanoresponses is stored as epigenetic and chromatin structure modifications. The mechanical state of the cell in response to the acellular and cellular environment also determines cell identity, fate, and immune response to invading pathogens. Here, we give a short overview of the latest developments in understanding these processes, emphasizing their effects on cell nuclei, chromosomes, and chromatin.

Topics: Chromatin; Humans; Cell Nucleus; Chromosomes; Animals; Mechanotransduction, Cellular; Stress, Mechanical; Cytoskeleton

PubMed: 40149890
DOI: 10.3390/biom15030354

Authors: Rachel Patton McCord, Yang Xu, Heng Li...

Chromosomes in higher eukaryotes are folded at different length scales into loop extrusion domains, spatial compartments, and chromosome territories and exhibit interactions with nuclear structures such as the lamina. Microscopic methods can probe this structure by measuring positions of chromosomes in the nuclear space in individual cells, while sequencing-based contact capture approaches can report the frequency of contacts of different regions within these structural layers. To view this SnapShot, open or download the PDF.

Topics: Cell Nucleus; Chromatin; Chromosomes; Eukaryota

PubMed: 35714589
DOI: 10.1016/j.molcel.2022.05.020

Review

Authors: Irina Solovei, Leonid Mirny

S.J. Gould and R. Lewontin in their famous "Spandrels paper" (1979) argued that many anatomical elements arise in evolution not due to their "current utility" but rather due to other "reasons for origin", such as other developmental processes, physical constraints and mechanical forces. Here, in the same spirit, we argue that a variety of molecular processes, physical constraints, and mechanical forces, alone or together, generate structures that are detectable in the cell nucleus, yet these structures themselves may not carry any specific function, being a mere reflection of processes that produced them.

Topics: Cell Nucleus; Animals; Humans

PubMed: 39180905
DOI: 10.1016/j.ceb.2024.102421