Nuclear-envelope proteins have been implicated in diverse and fundamental cell functions, among them transcriptional regulation. Gene expression at the territory of the nuclear periphery is known to be repressed by epigenetic modifications such as histone deacetylation and methylation. However, the mechanism by which nuclearenvelope proteins are involved in such modifications is still obscure. We have previously shown that LAP2␤, an integral nuclear-envelope protein that contains the chromatin-binding LEM domain, was able to repress the transcriptional activity of the E2F5-DP3 heterodimer. Here, we show that LAP2␤'s repressive activity is more general, encompassing various E2F members as well as other transcription factors such as p53 and NF-B. We further show that LAP2␤ interacts at the nuclear envelope with HDAC3, a class-I histone deacetylase, and that TSA (an HDAC inhibitor) abrogates LAP2␤'s repressive activity. Finally, we show that LAP2␤ is capable of inducing histone-H4 deacetylation. Our data provide evidence for the existence of a previously unknown repressive complex, composed of an integral nuclear membrane protein and a histone modifier, at the nuclear periphery.

The nuclear envelope (NE), which separates the nucleus from the cytoplasm, consists of the outer (ONM) and inner (INM) nuclear membranes and nuclear pore complexes (NPCs). The ONM is continuous with the endoplasmic reticulum (ER). The INM and ONM are separated by a lumenal space, but join at sites that are occupied by NPCs, which mediate bidirectional transport of macromolecules between the cytoplasm and the nucleus. The luminal space between the ONM and INM is crossed by giant protein complexes that bridge the NE and mechanically couple the cytoskeleton to the nucleoskeleton (reviewed in [1] The nuclear envelope (NE) is composed of inner and outer nuclear membranes (INM and ONM, respectively), nuclear pore complexes and an underlying mesh like supportive structure -the lamina. It has long been known that heterochromatin clusters at the nuclear periphery adjacent to the nuclear lamina, hinting that proteins of the lamina may participate in regulation of gene expression. Recent studies on the molecular mechanisms involved show that proteins of the nuclear envelope participate in regulation of transcription on several levels, from direct binding to transcription factors to induction of epigenetic histone modifications. Three INM proteins; lamin B receptor, lamina-associated polypeptide 2b and emerin, were shown to bind chromatin modifiers and ⁄ or transcriptional repressors inducing, at least in one case, histone deacetylation. Emerin and another INM protein, MAN1, have been linked to down-regulation of specific signaling pathways, the retino blastoma 1 ⁄ E2F MyoD and transforming growth factor beta ⁄ bone morphogenic protein, respectively. Therefore, cumulative data suggests that proteins of the nuclear lamina regulate transcription by recruiting chromatin modifiers and transcription factors to the nuclear periphery. In this minireview we describe the recent literature concerning mechanisms of gene repression by proteins of the NE and suggest the hypothesis that the epigenetic 'histone code', dictating transcriptional repression, is 'written' in part, at the NE by its proteins. Finally, as aberrant gene expression is one of the mechanisms speculated to underlie the newly discovered group of genetic diseases termed nuclear envelopathies ⁄ laminopathies, elucidating the repressive role of NE proteins is a major challenge to both researchers and clinicians.Abbreviations BAF, barrier-to-autointegration factor; EDMD, Emery-Dreifuss muscular dystrophy; GCL, germ cell less; HDAC, histone deacetylase; HP1, heterochromatin protein 1; IBSN, infantile bilateral striatal necrosis; INM, inner nuclear membrane; KASH, Klarsicht, ANC-1 and SYNE1 homology; LAP2b, lamina-associated polypeptide 2b; LBR, lamin B receptor; LEM domain, LAP2-emerin-MAN1 domain; ONM, outer nuclear membrane; NE, nuclear envelope; NES1, Nesprin-1; NES2g, Nesprin-2 giant; NPC, nuclear pore complexes; pRb, retinoblastoma protein; SREBP, sterol response element binding protein; SUN, S-phase arrest defective 1 and UNC-84 homology.; TGFb/BMP, transforming grow...

The nuclear envelope separates the chromosomes from cytoplasm in eukaryotic cells and consists of three main domains: inner and outer nuclear membranes and nuclear pore complexes. The inner nuclear membrane maintains close associations with the underlying chromatin and nuclear lamina. For many years, the nuclear envelope was thought to function mainly as an architectural stabilizer of the nucleus, participating in assembly and disassembly processes during mitosis. However, recent findings demonstrate that nuclear envelope proteins are involved in fundamental nuclear functions, such as gene transcription and DNA replication, and that inherited or de novo mutated proteins cause human diseases, termed "nuclear envelopathies." These findings emphasize the importance of understanding the functions of this cellular domain, in both physiologic and pathologic states. To date, mutations in the genes encoding the nuclear envelope proteins emerin, MAN1, lamin A/C, and lamin B receptor were found to cause nuclear envelopathies. The diseases that are caused by mutations in LMNA gene are collectively called "laminopathies." Nuclear envelopathies have diverse clinical phenotypes, ranging from cardiac and skeletal myopathies to partial lipodystrophy, peripheral neuropathy, and premature aging. This raises the question of how do such ubiquitously expressed proteins give rise to tissue-specific disease phenotypes. One possible explanation is the involvement of nuclear envelope proteins in the regulation of gene transcription, a novel mechanism that has been the focus of research in our lab in recent years. In this review, we describe recent discoveries in the field of nuclear envelopathies and discuss current proposed pathophysiological mechanisms underlying these diseases.