MINIREVIEW The nuclear lamina Both a structural framework and a platform for genome organization Joanna M. Bridger 1 , Nicole Foeger 2 , Ian R. Kill 1 and Harald Herrmann 3 1 Centre for Cell and Chromosome Biology, Division of Biosciences, Brunel University, London, UK 2 Institute for Medical Biochemistry, Vienna Biocenter, Austria 3 Functional Architecture of the Cell, German Cancer Research Center (DKFZ), Heidelberg, Germany Evolution of the intermediate filament protein family The nuclear lamina is a complex ensemble of proteins that connects the inner nuclear membrane to chroma- tin, and thus creates a link from the cytoplasm to the genome. The nuclear lamina has received much atten- tion recently, because presently 220 mutations have been discovered within one of the constituent polypep- tides, lamin A ⁄ C, and these have been demonstrated to be the cause of a number of severe human diseases, termed laminopathies (for a recent review see [1]). Moreover, their down-regulation is associated with specific cancers, such as lymphoma and leukaemia [2], and lung cancer [3]. In contemporary metazoan cells the lamina is com- prised of fibrous polypeptides of the intermediate filament (IF) protein family, one type in lower phyla like cnidaria or nematodes and four major forms in mammals, designated A-type (lamin A and lamin C) and B-type (lamin B1 and lamin B2), in addition to an increasing number of associated proteins [4]. Lamins were originally isolated from the high salt ⁄ detergent- insoluble fractions of nuclear envelopes derived from rat liver and named according to their apparent molecular mass during SDS ⁄ PAGE [5]. Moreover, B-type lamins are acidic and A-type lamins are basic, as revealed by isoelectric focusing in conventional two- dimensional polyacrylamide gel electrophoresis [6]. Molecular cloning as well as their appearance in the Keywords chromosomal organization; fluorescence in situ hybridization; intermediate filaments; lamins; nuclear envelope Correspondence H. Herrmann, B065 Functional Architecture of the Cell, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany Fax: +49 62214 23519 Tel: +49 62214 23512 E-mail: h.herrmann@dkfz-heidelberg.de (Received 26 February 2006, accepted 8 January 2007) doi:10.1111/j.1742-4658.2007.05694.x The inner face of the nuclear envelope of metazoan cells is covered by a thin lamina consisting of a one-layered network of intermediate filaments inter- connecting with a complex set of transmembrane proteins and chromatin associating factors. The constituent proteins, the lamins, have recently gained tremendous recognition, because mutations in the lamin A gene, LMNA, are the cause of a complex group of at least 10 different diseases in human, inclu- ding the Hutchinson–Gilford progeria syndrome. The analysis of these dis- ease entities has made it clear that besides cytoskeletal functions, the lamina has an important role in the ‘behaviour’ of the genome and is, probably as a consequence of this function, intimately involved in cell fate decisions. Fur- thermore, these functions are related to the involvement of lamins in organ- izing the position and functional state of interphase chromosomes as well as to the occurrence of lamins and lamina-associated proteins within the nucleo- plasm. However, the structural features of these lamins and the nature of the factors that assist them in genome organization present an exciting challenge to modern biochemistry and cell biology. Abbreviations IF, intermediate filament; LAP, lamina-associated protein; LBR, lamin B receptor. 1354 FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS electron microscope indicated that they are bona fide IF proteins, although distinct differences became clear both from the amino acid sequences and electron microscopic images [7–9]. With the availability of increasing sequence data for the IF multigene family, they were grouped into the so-called sequence homology class V, thereby distinguishing them from the cytoplasmic class I acidic keratins, the class II basic keratins, the class III desmin-like proteins and the class IV neuronal IF proteins [10,11]. In addition to carrying a conventional nuclear localization signal, lamins differ from the cytoplasmic IF proteins with respect to the structural organization in the first half of their central a-helical rod, which is 42 amino acids longer than that of cytoplasmic IF proteins (for review see [12]). This longer ‘rod’-version is also found in the cytoplasmic IF proteins of lower invertebrates and this led, together with data for the gene structure of various genes, to the concept that lamins, though they were detected last, were very probably the primordial IF proteins [13]. Hence, a speculative ancestral lamin gene stands at the origin of the 65 IF genes that we know for human at present [14]. The fact that human harbours only three genes for lamins – lamin A and C are derived by splicing from one gene – in contrast to more than 50 genes for keratins, may indicate that they are conserved with respect to the amino acid sequence for functional reasons and so their number did not increase in a corresponding fashion. Only in the germ cells of several vertebrates are additional spliced versions such as lamin C2 and lamin B3 are found. The fact that these special lamins are expressed in spermatocytes and oocytes possibly reflects the distinct organization of the nuclei of these cells in general and chromatin in particular in germ cells. Indeed, alteration of chromosome position- ing and reorganization of the genome is very noticeable during porcine spermatogenesis [15], with spermatogen- esis being perturbed in mice lacking A-type lamins [16]. A modulation of function, as required in various differentiated cells, may therefore be accomplished by a combination of various, differentially expressed associated proteins within or near the inner nuclear membrane [17]. Nevertheless, complex multicellular organisms such as Caenorhabditis elegans develop with one B-type lamin in their various differentiated cells [1]. Fibrous proteins: Structural properties and implications for function Lamins contain a central, mainly a-helical rod of 350 amino acids with four subsegments able to form coiled- coils with a like molecule in parallel orientation. These individual a-helical segments, coils 1A, 1B, 2A and 2B, are separated from each other by short ‘linkers’. The first (L1) and the third (L2) linker are probably a-helical whereas the second, longer one (L12) is unstructured [18]. Two such molecules are able to associate into an extended rod-like dimeric coiled-coil molecule of  50 nm length, and their formation has been demon- strated by glycerol spraying⁄ metal rotary shadowing EM techniques (for review see [19]). These experiments revealed also that the C-terminal domains of lamins form globular structures, which have recently been demonstra- ted by X-ray crystallography and NMR to be compact Ig folds [20,21]. Lamin dimers are stable under high pH and elevated salt conditions and this distinguishes them from cytoplasmic IF proteins such as vimentin, which form soluble, tetrameric complexes under low salt condi- tions, both at physiological and high pH. At higher salt concentration, i.e., 150–250 mm, vimentin will, however, associate into higher assemblies and eventually filaments [22,23]. Between the end of the a-helical rod and the Ig fold domain, a multitude of basic amino acids including a conventional nuclear localization signal is found, which may interact with the acidic patches of the rod domain. The non a-helical tail domain subsequent to the Ig fold domain has been demonstrated to harbour chro- matin-binding activity in a short glycine-serine-threonine rich element near the carboxy-terminus [24]. Assembly, topogenesis and interaction partners Assembly of intermediate filaments starts with the formation of coiled-coil dimers, which in the case of lamins preferentially associate head-to-tail to form extended threads of dimers [12,19]. Whether this occurs during translation or post-translationally is unknown. Moreover, it is completely unclear whether lamin B1 and lamin B2 associate into homodimers exclusively or if they are able – or even prefer – to form heterodimers. With respect to the behaviour of lamins during mitosis, i.e., A-type lamins being found in a soluble and B-type lamins in a membrane-bound form, it is rather safe to postulate that A- and B-type lamins segregate completely within the cell, at least at the dimeric level (Fig. 1; see Fig. 4 in [25]). Moreover, during embryogenesis B-type lamins suffice to facilitate proper development as demonstrated by gene targeting of lamin A in mice [26]. At what level lamin B1 and lamin B2 interact, is presently not known. Due to the high sequence identity within the coiled-coil forming domain of both lamins, it may be safe to speculate that they are able to associate into mixed dimers. With the onset of mitosis, the lamina is disassembled due to specific phosphorylation reactions, and is, upon J. M. Bridger et al. The nuclear lamina FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS 1355 completion of mitosis, reorganized on the surface of individual chromosomes together with inner nuclear membrane proteins such as lamin B receptor (LBR), emerin and lamina-associated protein (LAP)s ([27], for review see [28,29]). Their function during this period of the cell cycle is elusive. It may be that this cell cycle stage provides the cell with a possibility to reorganize the nucleus, allowing genome organization within nuc- lei to be drastically altered. It is interesting to note that if a quiescent state of chromosome positioning within nuclei is enforced by serum starvation, it is not until the next postmitotic G1 phase that the chromosomes are found repositioned in a proliferating organization [30]. Genome organization and the nuclear lamina One of the enigmatic suggested roles for lamins is in genome organization, which could impact on regulation of genome function, i.e., gene expression [31]. Indeed, all the lamin subtypes have affinity for chromosomes, chromatin and ⁄ or DNA [24,32–35]. Because chromatin and the nuclear lamina exhibit an intimate spatial relationship, it has been suggested that chromosomes are anchored, at least to some extent, by the nuclear lamina [31,36]. Chromosome positioning within nuclei is nonrandom and in human lympho- blasts and fibroblasts chromosomes are positioning according to their gene-density [37,38], with the most gene-poor chromosomes found at the nuclear periph- ery abutting the nuclear lamina (Fig. 2). It is as yet unclear whether the nonrandom spatial positioning of the genome within nuclei is involved in controlling gene expression, but alterations in the level of tran- scription have been observed when specific loci change position within nuclei [39]. On the other hand it may be that chromosomes themselves do not move much within nuclei once they are positioned but specific gene sequences may be looped towards areas of the nucleus more amenable to transcription [31]. However, the question still remains as to whether the nuclear lamina anchors specific chromosomes within nuclei and whether this is relevant to the con- trol of gene expression. We have assessed the posi- tioning of specific chromosomes within cells that do not appear to express A-type lamins and in human studies we find little difference in the positioning of four gene-poor chromosomes at the nuclear periphery AB Fig. 1. Solubility properties of lamins in human cultured cells. (A) High salt ⁄ Triton X100 resistant fraction of SW13 cells (left lane) and human dermal fibroblasts (right lane) separated on 20 cm long 10% polyacrylamaide gels [67]. Lamins are indicated by dots (A, B1, B2 and C from top to bottom), vimentin by an arrowhead. Note the very low amount of lamins compared to the cytoplasmic intermediate filament protein vimentin. (B) Immunoblot of low salt- soluble (lane 1), high salt-soluble and high salt ⁄ Triton X100 resistant protein fractions of SW13 cells. Aliquot fractions were generated according to a standard extraction protocol [67], separated by elec- trophoresis on 10% polyacrylamide gels and either stained with Coomassie Brilliant Blue (CBB) or blotted and immunostained employing specific antibodies to lamin A (La A), lamin B1 (La B1), lamin B2 (La B2) and LBR. The right panels of the immunoblots are longer exposures of the corresponding left panels. Note that lamin B1 is partially extracted into the low salt ⁄ Triton X100 fraction. Fig. 2. Chromosome territories. A human nucleus with two individ- ual chromosome territories revealed after painting with a whole human chromosome painting probe by fluorescence in situ hybrid- ization (green). The total amount of the DNA is delineated by the fluorescent DNA stain DAPI (blue). Image from Ishita Mehta (Divi- sion of Biosciences, Brunel University, London, UK). Bar ¼ 10 lm. The nuclear lamina J. M. Bridger et al. 1356 FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS in lymphoblastoid cell lines from patients with lam- in A mutations [40]. One gene-poor chromosome (chromosome 13), however, was found located away from the nuclear periphery in two patient cell lines. Interestingly, the lamin A mutation in these two cell lines was within a DNA ⁄ chromatin binding domain [35]. Further, we have found that in cells lacking A-type lamins within the nuclear lamina, such as porcine pri- mary ex vivo lymphocytes, there are fewer chromo- somes located at the nuclear periphery. Thus, in porcine lymphocytes many of the chromosomes that are normally located abutting the nuclear lamina in other cell types containing A-type lamins, are located away from the nuclear edge (Foster H, Griffin D and Bridger J, unpublished data). Taken together these two pieces of data could imply that in disease cells and nondisease cells of the haemopoietic lineage lacking A-type lamins, a distinct alteration in chromosome anchorage at the nuclear periphery may occur. The role of the A-type lamin containing structures may not be purely anchorage but there may be, in addition, more subtle changes that are not elicited purely as alternative chromosome location. We have determined phases and stages in a cell’s life where chromosome positioning is completely altered from that of a young proliferating cell, namely quiescence [30] and senescence ([30,41]; Bridger J, unpublished data) or in differentiating precursor cells, i.e., in spermatogenesis [15]. These drastic alterations in chromosome positioning do coincide with changes in lamin complement in spermatogenesis [42] and poss- ible lamin interaction with chromatin in quiescence [43]. It is interesting to note that territories of chromo- some 18, normally positioned at the nuclear periphery, are repositioned to the nuclear interior in cells induced to enter quiescence by serum starvation, but do not relocate to the nuclear periphery until after a mitosis following restimulation of the cells by the addition of serum [30]. Hence, chromosome 18 can probably relocate in proliferating cells only because the interac- tion with nuclear lamina components becomes possible during the rebuilding of the nucleus at mitosis. In primary fibroblast cell lines derived from patients with laminopathies, i.e., mutations in lamin A, we have also observed major changes in chromosome position- ing, away from the nuclear periphery, however, these cells appear to have A-type lamins as part of the nuc- lear lamina [41]. These data assessing whole chromo- some positioning support other studies in laminopathy cell lines whereby chromatin is disorganized and observed coming away from the nuclear periphery [27,44–46]. Chromatin disorganization is also seen in C. elegans worms that have their lamin expression down-regulated [47]. Despite the small amount of evidence one may hypothesize that nuclear lamin subtypes do play a role in genome organization in the various cell cycle phases, life cycle stages, cell lineage and differentiation states. A functional interactive nuclear lamin network Early investigations described the lamina as a 15 nm thick proteinaceous layer co-isolating with the nuclear pore complexes [48]. Although electron microscopy of thin-sectioned nuclei of cells and tissues indicated the existence of a continuous layer of proteins apposed to the inner membrane of the nuclear envelope, in the vast majority of cells the nuclear lamina cannot be resolved as such a distinct structure separating the chromatin from the nuclear envelope. However, in some special cell types of both invertebrate and verte- brate origin, a lamina of 30–300 nm isolating the inner nuclear membrane and chromatin can be visualized. Most interestingly, in human synovial cells of patients suffering from rheumatoid arthritis, a 50–70 nm thick lamina containing lamin proteins can be observed [49]. Both B-type and A-type lamins can be found not only at the nuclear periphery but also within nuclei localized as internal foci [50–52]. Most attention has focused on the A-type lamin foci. The function of these internal lamin sites is not really determined but they can also contain transcription factors [53] and important proteins associated with cell proliferation such as the retinoblastoma protein pRb [54]. In addi- tion, these internal lamin structures contain lamina- associated protein 2a (LAP2a), a protein with distinct chromatin binding abilities [55]. Thus, there are sites deep within nuclei that have putative chromatin ⁄ chro- mosome binding and anchorage abilities. There are even studies that display a networked filamentous structure anatomising through nuclei, namely the nuc- lear matrix, containing A-type lamins [56–58]. It has been shown that even the internal lamin structures are affected in cells that contain mutation in the LMNA gene [59]. Whether internal lamins are only found in particular foci or in a structured nuclear matrix is, however, still debated. Nevertheless, both biochemical and microscopic data indicate that lamins are present throughout the nucleus. Without knowing their ultra- structural state, one may consider that these lamin foci are anchor points for the genome and that they could be involved in the control of genome function. Such a ‘network’ comprised of lamins and chromatin could be thought of as ‘intelligent scaffolding’ (Fig. 3). This net- J. M. Bridger et al. The nuclear lamina FEBS Journal 274 (2007) 1354–1361 ª 2007 The Authors Journal compilation ª 2007 FEBS 1357 work may furthermore be restructured dynamically during different phases of the cell cycle and therefore exhibit a different appearance in individual cells in nonsynchronized cell cultures. Outlook The nuclear lamins are a very interesting group of structural proteins that appear to have many functions. Perhaps one of the most difficult to study functions is the role within interphase genome organization and their influence over genome function. It appears from our studies that A-type lamins influence chromosome position within interphase nuclei. How this happens and what the consequences for genome function are remains to be elucidated. It is also plausible that the A-type la- mins are not purely anchorage sites for the genome but perhaps they are involved in a signalling pathway that is perturbed in diseased cells, falsely changing the cellular status and eliciting a reorganization of the genome. Indeed, signals received within the cytoplasm could be translocated to the genome and translated by a linked pathway of proteins from the cytoskeleton, across the nuclear membrane to the nuclear lamin structures [60]. The existence of a structurally unified system consisting of DNA, scaffold proteins and the surrounding cytoske- leton has been proposed on the grounds of very interest- ing data [61]. Moreover, it has been hypothesized for many years that the cytoplasmic intermediate filament system is determining and supporting the position of the nucleus in the cell [62,63]. Now, the recent identification of an interaction between the outer nuclear membrane protein nesprin 3 and the intermediate filament-associ- ated protein plectin provides direct support for such a role [64]. M oreover, as cytoplasmic p roteins such as v imen- tin and plectin are subject to multiple phosphorylation reactions [65,66], a link between the structural and the signalling state of the cytoskeleton with mechanisms that control gene expression is open for investigation. Acknowledgements We wish to thank Peter Lichter for continuous interest and support. JMB gratefully acknowledges support from Sygen International PLC and Brunel University. NF received a fellowship from the Schroedinger pro- gramme (FWF, Austria). 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