Gene silencing at the nuclear periphery.

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 2beta 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.