NET gains and losses: the role of changing nuclear envelope proteomes in genome regulation

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In recent years, our view of the nucleus has changed considerably with an increased awareness of the roles dynamic higher order chromatin structure and nuclear organization play in nuclear function. More recently, proteomics approaches have identified differential expression of nuclear lamina and nuclear envelope transmembrane (NET) proteins. Many NETs have been implicated in a range of developmental disorders as well as cell-type specific biological processes, including genome organization and nuclear morphology. While further studies are needed, it is clear that the differential nuclear envelope proteome contributes to cell-type specific nuclear identity and functions. This review discusses the importance of proteome diversity at the nuclear periphery and highlights the putative roles of NET proteins, with a focus on nuclear architecture.

Introduction

The nucleus, as an organelle, does more than simply house the genetic material of an organism. The nucleus is itself an interpreter and regulator of cell type specific functions and, as such, is unique between cell types. In addition to expressing cell type specific transcription factors and genome regulators, this diversity is also quite evident at the peripheral zone of the nucleus. The nuclear periphery encompasses the nuclear envelope and the underlying nuclear lamina [1]. The nuclear envelope is a dual membrane barrier, comprised of the inner nuclear membrane (INM) and the outer nuclear membrane (ONM). These membranes are studded with nuclear pore complexes that span from the cytosol into the nucleoplasm and the ONM; hence the nuclear envelope is contiguous with the endoplasmic reticulum (ER). The nuclear lamina is a proteinaceous meshwork of type V intermediate filaments, the lamins, which have two classes: A-type and B-type [1, 2, 3]. In mammals, the major A type lamins, lamins A and C, are isoforms derived from alternatively spliced products of the same gene — LMNA [4, 5]. The major B type lamins (B1 and B2), however, are derived from different genes: LMNB1 and LMNB2, respectively [6, 7]. The INM and the nuclear lamina are interdependent structures held together by mutual molecular interactions between the INM proteins and the underlying lamina meshwork [8, 9••]. These interactions appear to facilitate the retention of INM proteins that would otherwise freely diffuse throughout the INM, ONM, and ER continuum. Therefore, in normal nuclei, in spite of the continuity of the INM and the ONM, these two compartments harbor different complements of proteins and are thus functionally distinct [8].

Despite the importance of the nucleus in normal cell physiology and function, prior to 2003 only a handful of proteins and their spliceoforms had been identified and characterized as nuclear envelope proteins [10••]. Advances in proteomics research has allowed for a massive expansion of this list of nuclear periphery resident proteins. More recently, high throughput approaches have been used to characterize and compare the differential nuclear proteome between tissues and between cellular states [11••, 12••, 13••]. These explorations have demonstrated that the protein landscape of the nuclear membrane is quite diverse and expanded our view of the role that the nuclear periphery may play in normal cellular functions. Such a highly diverse proteome, in conjunction with tissue specific genome regulators and transcription factors, would further enable the nucleus to perform its various biological roles in a cell/tissue specific manner in response to cell/tissue specific requirements. Moreover, the involvement of the nuclear periphery in development and homeostasis is exemplified by a number of developmental disorders arising from mutations in proteins of the nuclear envelope and lamina, collectively termed the Nuclear Envelopathies [14, 15]. Clinical phenotypes of these diseases include cardiac and skeletal muscular dystrophies, dermopathies, peripheral neuropathies, lipodystrophies and premature aging [14, 15]. Clinical investigations of these Envelopathies and basic biological research on the nuclear periphery have reached a consensus that the nuclear lamina and envelope exert tremendous influence on signaling cascades, mechanical integrity, and, importantly, nuclear architecture and gene regulation [16, 17, 18, 19••, 20, 21] (Figure 1, Table 1).

Section snippets

Nuclear architecture: chromatin and chromosomal domains

The dynamic organization and architecture of the nucleus contributes to regulation of gene expression during normal cellular function, in development, and its disorganization has been implicated in disease. In eukaryotic cells, DNA is organized into chromatin that is comprised of nucleosomes characterized to be 146 bases of DNA wrapped 1.65 times around a histone octamer consisting of two H2A and B heterodimers and a histone H3/H4 tetramer [22]. These nucleosomes are then packaged into

Cell type specific nuclear architecture

There are a large number of studies demonstrating that the organization of chromatin is both dynamic and structured. For example, individual chromosomes in interphase nuclei are organized and occupy regions defined as chromosome territories (CT), which can be observed by using labeled DNA or oligo probes that cover most of the chromosome (often referred to as ‘chromosome paints’) [24, 25]. The disposition of CTs in the nucleus is dependent on gene density, with gene-poor chromosomes tending to

Proteomic diversity at the nuclear envelope

Interestingly, a number of the proteins that are resident to the peripheral zone of the nucleus — the lamins and nuclear membrane associated proteins and NETs — are differentially expressed [11••, 12••, 13••, 59••, 63, 64, 65, 66, 67, 68•] (Figure 2). For example, the composition of the lamina meshwork has been found to be different between cell types. In brain, the lamin C isoform of the LMNA gene is widely expressed whereas the expression of the lamin A spliceoform is absent in neurons and

NET diversity and nuclear architecture

Clearly, both genome organization and protein composition at the nuclear periphery change with differentiation and cellular state. As discussed above, the mechanism of positioning and maintenance of large chromosomal regions at the nuclear periphery is a subject of intense investigation. Such subchromosomal domain positioning is likely to rely on a combination of chromatin modifications, DNA sequence, DNA or chromatin binding proteins and proteins of the INM/lamina. To this end, a handful of

Diseases of the nuclear periphery

Given the involvement of the nuclear periphery in a multitude of cellular processes, it is perhaps not surprising that proteins at the nuclear periphery have been implicated in a range of developmental diseases. It is thus not far-fetched to speculate that differential NET composition will impact the severity, penetrance and tissue specificity of these diseases. These Nuclear Envelopathies are sometimes referred to as laminopathies, although the latter usually refers specifically to mutations

Summary and future directions

The nucleus of each cell type is unique and this is also evident in the proteome of the nuclear envelope. The advent of tissue and cell type specific whole cell proteome mapping along with more targeted approaches to identifying novel NET proteins will likely lead to a greater understanding of normal development progression and anomalies regulated by proteins at the INM. Expanding the universe of tissue/cell type specific NETs, and their relationship with cell specific genome organization, will

References and recommended reading

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

  • of special interest

  • of outstanding interest

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