Genome–nuclear lamina interactions and gene regulation

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The nuclear lamina, a filamentous protein network that coats the inner nuclear membrane, has long been thought to interact with specific genomic loci and regulate their expression. Molecular mapping studies have now identified large genomic domains that are in contact with the lamina. Genes in these domains are typically repressed, and artificial tethering experiments indicate that the lamina can actively contribute to this repression. Furthermore, the lamina indirectly controls gene expression in the nuclear interior by sequestration of certain transcription factors. A variety of DNA-binding and chromatin proteins may anchor specific loci to the lamina, while histone-modifying enzymes partly mediate the local repressive effect of the lamina. Experimental tools are now available to begin to unravel the underlying molecular mechanisms.

Introduction

The cell nucleus is enclosed by a double lipid bi-layer with interspersed nuclear pore complexes (NPCs) that facilitate selective nuclear-cytoplasmic exchange of macromolecules. In metazoans, the nucleoplasmic surface of the inner nuclear membrane (INM) is structurally supported by the nuclear lamina (NL), a filamentous meshwork consisting of specialized intermediate filament proteins named lamins. There are two types of lamins: B-type lamins are found in all cell types, whereas the A-type lamins are found only in differentiated cells [1, 2]. Lamins interact with many other proteins, some of which are integral components of the INM [1, 3]. A wide spectrum of human disorders has been linked to mutations in lamins or lamin-interacting proteins [4], illustrating the importance of the NL.

For decades it has been thought that the NL may act as a surface for the anchoring of specific DNA sequences, thereby providing a scaffold for the folding of chromosomes inside the nucleus. In addition, the NL may play an active role in the regulation of gene expression. Recent microscopy studies, gene-tethering approaches and the mapping of genome–NL interactions at molecular resolution have yielded new insights into these processes. In this review we discuss the possible roles of the NL in chromosome organization and transcriptional regulation, with emphasis on new data reported over the past two years.

Section snippets

The genome in association with the NL and the NPC

Classic electron micrographs [5] and recent high-resolution light microscopy images of mammalian cell nuclei [6] show that the NL tends to be in close contact with relatively compact chromatin, while NPCs are surrounded by much less, or decondensed, chromatin. Genome-wide mapping using the DamID technology has identified the regions of the genome that are in molecular contact with the NL in both human and fly cells [7, 8•]. Human fibroblasts have more than 1300 of such genomic contact regions,

Mechanisms of genome–NL interactions

Do LADs adhere to the NL owing to specific biochemical interactions, or are they passively pushed towards the periphery because other chromosomal regions have a preference to be located in the nuclear interior? Interesting new computer simulations of chromosome polymer dynamics suggest that local differences in certain basic physical properties of the chromatin fiber, such as flexibility and thickness, may partly drive the peripheral location of heterochromatin by self-organization principles [

Rebuilding genome–NL interactions after mitosis

During mitosis, phosphorylation of NPC-components and NL-components initiates the disassembly of the nucleus [29, 30] and results into the dissociation of INM proteins and lamins from chromatin [31]. As cells need to progress through cell division for de novo NL–genome interaction to occur, the nuclear architecture is probably established during nuclear reassembly [32••, 33••]. The molecular basis for the reassembly of the nuclear envelope at the end of mitosis is not understood in great

Gene regulation by the NL

Does the NL play an active role in gene regulation, or is it merely an innocent bystander? Microarray and in situ expression analyses have shown that the depletion of lamins and other NL proteins causes misregulation of hundreds of genes [20, 23, 39, 40, 41], as does expression of a lamin A mutant that causes premature aging in humans [42]. In Drosophila, the knockdown of the only B-type lamin causes derepression of a testis-specific gene cluster, together with the relocalization of this

Conclusions

The availability of new tools, such as molecular tethering methods, genome-wide mapping techniques, and subdiffraction light microscopy, has created exciting new opportunities to dissect the causal relationships among genome–NL interactions, interphase chromosome folding, and gene regulation in mammalian cells. A picture emerges in which the NL contributes to the spatial organization of the genome and helps to repress genes that are in close proximity. DNA-binding factors as well as chromatin

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to colleagues whose work we could not discuss owing to space constraints. We thank G. Filion, W. Meuleman, U. Braunschweig, and A. Pindyurin for helpful comments, and the M. Fornerod, M. Hetzer, A. Akhtar, and L. Wallrath labs for sharing unpublished results. Supported by an EMBO Long-term Fellowship to JK and an NWO-VICI grant to BvS.

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