Spatial chromatin organization and gene regulation at the nuclear lamina
Introduction
The NL is a thin meshwork of type V intermediate lamin filaments that coat the INM with the exception of sites of nuclear pore complexes (NPCs). The NL in mammalian cells consist of A-type and B-type lamins and many associated proteins including proteins that are integral components of the INM [1]. The protein constitution of the NL-meshwork can vary extensively between cell types and A-type lamin protein levels are generally strongly reduced in undifferentiated cell types. In accordance with observations of classical electron micrographs [2], it has long been recognized that the chromatin in proximity to the NL is in a condensed state. More recently, a novel method that combines DNA-labelling and three-dimensional electron microscopy (ChromEMT) revealed that chromatin is organized into 5-nm–24-nm nucleosomal chains with increased packaging densities at the NL [3•]. By employing the DamID technology, the identity of the genomic regions that contact the NL was first revealed in Drosophila melanogaster [4]. Since this first report, LADs have been further characterized in the fruit fly but also in Caenorhabditis elegans and multiple mammalian cell types [4, 5, 6, 7]. LADs are of particular interest because, in addition to playing an important role in genome architecture, regions that contact the NL differ with respect to cell type-specific gene expression, suggesting a role for LADs in gene regulation [7,8]. This review will focus on the molecular mechanisms that may be involved in the organization of LADs and the possible contributions of genome–NL contacts to the regulation of transcription during cellular differentiation and development.
Section snippets
Genome organization at the NL
In mammalian cells, the genome contains approximately 1000–1500 LADs with a median domain size of ∼0.5 Mb [5,7]. In addition to lamina association, chromatin has been shown to be structured in the three dimensional nuclear space in topologically associating domains (TADs), characterized by a high level of intra-domain contacts in contrast with few interactions occurring between TADs [9]. At a larger scale, TADs have been grouped into A and B compartments, corresponding to active and inactive
Mechanisms of LAD formation
Multivalent interactions of A/T rich regions appear to support robust NL-associations, but what are the anchors that mediate these contacts? Lamins could directly mediate tethering as they have been shown to bind chromatin and DNA [15,16]. Indeed, in Drosophila, depletion of the B-type lamin causes detachment of certain gene loci from the nuclear periphery in S2 cells [17]. Similarly, loss of the sole lamin protein in C. elegans causes perinuclear release of large heterochromatic arrays [18].
LADs and the regulation of gene expression
Genes within LADs are generally lowly transcribed, which is suggestive of a role for LADs in gene silencing. The role of the NL in gene regulation may entail direct involvement in gene repression, for example, by exclusion of genes from the transcriptionally active nuclear interior, and/or indirect via the reinforcement or locking in of chromatin states. Random genomic integrations of thousands of reporters resulted in ∼5–6-fold attenuation of gene activity when inserted in LADs relative to
Conclusions
Genome-nuclear lamina interactions play an important structural role in the three-dimensional organization of the genome and are likely to be involved in gene regulation. The integration of new insights into a preexisting framework of literature reveals a scenario whereby NL composition, chromatin state of LADs and presence of DNA-binding proteins cooperatively regulate gene expression at the nuclear periphery.
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank the members of the Kind group for critical reading of the manuscript. This work was supported by a Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) VIDI (016.161.339) and ERC-Stg EpiID (678423) grant to J.K. and an EMBO ALTF 1214-2016 fellowship to I.G. The Oncode Institute is supported by KWF Dutch Cancer Society.
References (65)
- et al.
Nuclear lamins: thin filaments with major functions
Trends Cell Biol
(2018) - et al.
Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence
Genome Res
(2013) - et al.
The insulator protein SU(HW) fine-tunes nuclear lamina interactions of the Drosophila genome
PLoS One
(2010) - et al.
High-resolution whole-genome sequencing reveals that specific chromatin domains from most human chromosomes associate with nucleoli
Mol Biol Cell
(2010) - et al.
Nuclear aggregation of olfactory receptor genes governs their monogenic expression
Cell
(2012) - et al.
LBR and lamin A/C sequentially tether peripheral heterochromatin and inversely regulate differentiation
Cell
(2013) - et al.
Loss of lamin B receptor is necessary to induce cellular senescence
Biochem J
(2017) - et al.
Massive reshaping of genome–nuclear lamina interactions during oncogene-induced senescence
Genome Res
(2017) - et al.
Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain
Nature
(2001) - et al.
Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells
Nat Genet
(2009)
Systematic protein location mapping reveals five principal chromatin types in Drosophila cells
Cell
The large fraction of heterochromatin in Drosophila neurons is bound by both B-type lamin and HP1a
Epigenetics Chromatin
Comprehensive analysis of the chromatin landscape in Drosophila melanogaster
Nature
Global chromatin architecture reflects pluripotency and lineage commitment in the early mouse embryo
PLoS One
Genome-wide chromatin state transitions associated with developmental and environmental cues
Cell
On the occurrence of a fibrous lamina on the inner aspect of the nuclear envelope in certain cells of vertebrates
Am J Anat
ChromEMT: visualizing 3D chromatin structure and compaction in interphase and mitotic cells
Science
Characterization of the Drosophila melanogaster genome at the nuclear lamina
Nat Genet
Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions
Nature
Caenorhabditis elegans chromosome arms are anchored to the nuclear membrane via discontinuous association with LEM-2
Genome Biol
Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation
Mol Cell
Topological domains in mammalian genomes identified by analysis of chromatin interactions
Nature
Genome-wide maps of nuclear lamina interactions in single human cells
Cell
Single-cell dynamics of genome-nuclear lamina interactions
Cell
Initial genomics of the human nucleolus
PLoS Genet
The carboxyl-terminal region common to lamins A and C contains a DNA binding domain
Biochemistry
The alpha-helical rod domain of human lamins A and C contains a chromatin binding site
EMBO J
The B-type lamin is required for somatic repression of testis-specific gene clusters
Proc Natl Acad Sci U S A
Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery
Cell
Lamins organize the global three-dimensional genome from the nuclear periphery
Mol Cell
The molecular architecture of lamins in somatic cells
Nature
Structural organization of nuclear lamins A, C, B1, and B2 revealed by superresolution microscopy
Mol Biol Cell
Cited by (31)
3D spatial genome organization in the nervous system: From development and plasticity to disease
2022, NeuronCitation Excerpt :In one exception, this organization is inverted in rod photoreceptor neurons of nocturnal retinas, in which the dense heterochromatin localized in the nuclear center may serve as collecting lenses to enhance light transduction efficiency (Falk et al., 2019; Sofueva et al., 2013; Solovei et al., 2009). Lamina-associated domains (LADs), which are genomic regions that are in close contact with the nuclear lamina, are also thought to help organize chromosomes inside the nucleus and have been largely associated with gene repression (Guerreiro and Kind, 2019; van Steensel and Belmont, 2017). Since the initial 3C technology, various methodologies have been developed to investigate chromatin architecture.
Nuclear envelope remodelling during mitosis
2021, Current Opinion in Cell BiologyGenetic approaches to revealing the principles of nuclear architecture
2021, Current Opinion in Genetics and DevelopmentCitation Excerpt :Additionally, many genomic loci are nonrandomly positioned within the 3D nuclear volume [2,3]. This organization is likely driven by regions of chromosomes that are sequestered at the nuclear envelope or that interact with more fixed structures and/or nuclear bodies (i.e. nuclear pore complexes, the nucleolus or splicing speckles) [3–5]. These nuclear bodies are composed of factors specific for the function the structure carries out.
Structure and unique mechanical aspects of nuclear lamin filaments
2020, Current Opinion in Structural BiologyNuclear mechanotransduction in stem cells
2020, Current Opinion in Cell BiologyViewing Nuclear Architecture through the Eyes of Nocturnal Mammals
2020, Trends in Cell BiologyCitation Excerpt :This may limit the options for spatial regulation of transcription [39–41], or efficient DNA repair of double-strand breaks (DSBs) [42] (e.g., by reducing the efficiency of interactions between homologous chromosomes for DSB repair). Moreover, the lack in inverted nuclei of HC tethering to the nuclear lamina, which is widely accepted as a major mechanism of gene silencing and suppression of mobile elements [43], might be another strong drawback rendering inverted nuclei disadvantaged. Another known example of nuclei without intra- and interchromosomal interactions and without a broad contact with the nuclear envelope is found in Diptera somatic cells containing polytene chromosomes [44,45].