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      Lamina-associated domains: peripheral matters and internal affairs

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          Abstract

          At the nuclear periphery, associations of chromatin with the nuclear lamina through lamina-associated domains (LADs) aid functional organization of the genome. We review the organization of LADs and provide evidence of LAD heterogeneity from cell ensemble and single-cell data. LADs are typically repressive environments in the genome; nonetheless, we discuss findings of lamin interactions with regulatory elements of active genes, and the role lamins may play in genome regulation. We address the relationship between LADs and other genome organizers, and the involvement of LADs in laminopathies. The current data lay the basis for future studies on the significance of lamin-chromatin interactions in health and disease.

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          Genome architecture: domain organization of interphase chromosomes.

          The architecture of interphase chromosomes is important for the regulation of gene expression and genome maintenance. Chromosomes are linearly segmented into hundreds of domains with different protein compositions. Furthermore, the spatial organization of chromosomes is nonrandom and is characterized by many local and long-range contacts among genes and other sequence elements. A variety of genome-wide mapping techniques have made it possible to chart these properties at high resolution. Combined with microscopy and computational modeling, the results begin to yield a more coherent picture that integrates linear and three-dimensional (3D) views of chromosome organization in relation to gene regulation and other nuclear functions. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Transcriptional repression mediated by repositioning of genes to the nuclear lamina.

            Nuclear compartmentalization seems to have an important role in regulating metazoan genes. Although studies on immunoglobulin and other loci have shown a correlation between positioning at the nuclear lamina and gene repression, the functional consequences of this compartmentalization remain untested. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM), and tested the consequences of such repositioning on gene activity in mouse fibroblasts. Here, using three-dimensional DNA-immunoFISH, we demonstrate repositioning of chromosomal regions to the nuclear lamina that is dependent on breakdown and reformation of the nuclear envelope during mitosis. Moreover, tethering leads to the accumulation of lamin and INM proteins, but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Finally, we use targeted adenine methylation (DamID) to show that, as is the case for our model system, inactive immunoglobulin loci at the nuclear periphery are contacted by INM and lamina proteins. We propose that these molecular interactions may be used to compartmentalize and to limit the accessibility of immunoglobulin loci to transcription and recombination factors.
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              Genome-wide maps of nuclear lamina interactions in single human cells.

              Mammalian interphase chromosomes interact with the nuclear lamina (NL) through hundreds of large lamina-associated domains (LADs). We report a method to map NL contacts genome-wide in single human cells. Analysis of nearly 400 maps reveals a core architecture consisting of gene-poor LADs that contact the NL with high cell-to-cell consistency, interspersed by LADs with more variable NL interactions. The variable contacts tend to be cell-type specific and are more sensitive to changes in genome ploidy than the consistent contacts. Single-cell maps indicate that NL contacts involve multivalent interactions over hundreds of kilobases. Moreover, we observe extensive intra-chromosomal coordination of NL contacts, even over tens of megabases. Such coordinated loci exhibit preferential interactions as detected by Hi-C. Finally, the consistency of NL contacts is inversely linked to gene activity in single cells and correlates positively with the heterochromatic histone modification H3K9me3. These results highlight fundamental principles of single-cell chromatin organization. VIDEO ABSTRACT.
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                Author and article information

                Contributors
                philippe.collas@medisin.uio.no
                Journal
                Genome Biol
                Genome Biol
                Genome Biology
                BioMed Central (London )
                1474-7596
                1474-760X
                2 April 2020
                2 April 2020
                2020
                : 21
                : 85
                Affiliations
                [1 ]GRID grid.5510.1, ISNI 0000 0004 1936 8921, Department of Molecular Medicine, Faculty of Medicine, , University of Oslo, ; PO Box 1112 Blindern, 0317 Oslo, Norway
                [2 ]GRID grid.55325.34, ISNI 0000 0004 0389 8485, Department of Immunology and Transfusion Medicine, , Oslo University Hospital, ; 0424 Oslo, Norway
                Article
                2003
                10.1186/s13059-020-02003-5
                7114793
                32241294
                0b5542fb-a037-4f5b-ba2f-154411692a17
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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                Review
                Custom metadata
                © The Author(s) 2020

                Genetics
                3d genome,chromatin,lad,lamin a mutation,nuclear envelope,nuclear lamin,radial positioning
                Genetics
                3d genome, chromatin, lad, lamin a mutation, nuclear envelope, nuclear lamin, radial positioning

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