Spatial chromatin organization and gene regulation at the nuclear lamina

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The nuclear lamina (NL) consists of a thin meshwork of lamins and associated proteins that lines the inner nuclear membrane (INM). In metazoan nuclei, a large proportion of the genome contacts the NL in broad lamina-associated domains (LADs). Contacts of the NL with the genome are believed to aid the spatial organization of chromosomes and contribute to the regulation of transcription. Here, we will focus on recent insights in the structural organization of the genome at the NL and the role of this organization in the regulation of gene expression.

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.

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