title: Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2.
abstract: Transcriptionally silent chromatin localizes to the nuclear periphery, which provides a special microenvironment for gene repression. A variety of nuclear membrane proteins interact with repressed chromatin, yet the functional role of these interactions remains poorly understood. Here, we show that, in Schizosaccharomyces pombe, the nuclear membrane protein Lem2 associates with chromatin and mediates silencing and heterochromatin localization. Unexpectedly, we found that these functions can be separated and assigned to different structural domains within Lem2, excluding a simple tethering mechanism. Chromatin association and tethering of centromeres to the periphery are mediated by the N-terminal LEM (LAP2-Emerin-MAN1) domain of Lem2, whereas telomere anchoring and heterochromatin silencing require exclusively its conserved C-terminal MSC (MAN1-Src1 C-terminal) domain. Particularly, silencing by Lem2 is epistatic with the Snf2/HDAC (histone deacetylase) repressor complex SHREC at telomeres, while its necessity can be bypassed by deleting Epe1, a JmjC protein with anti-silencing activity. Furthermore, we found that loss of Lem2 reduces heterochromatin association of SHREC, which is accompanied by increased binding of Epe1. This reveals a critical function of Lem2 in coordinating these antagonistic factors at heterochromatin. The distinct silencing and localization functions mediated by Lem2 suggest that these conserved LEM-containing proteins go beyond simple tethering to play active roles in perinuclear silencing.
authors.affiliation: Department of Physiological Chemistry, Biomedical Center, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany;
authors.forename: Ramón Ramos
authors.initials: RR
authors.lastname: Barrales
authors.affiliation: Department of Physiological Chemistry, Biomedical Center, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany;
authors.forename: Marta
authors.initials: M
authors.lastname: Forn
authors.affiliation: Department of Physiological Chemistry, Biomedical Center, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany;
authors.forename: Paula Raluca
authors.initials: PR
authors.lastname: Georgescu
authors.affiliation: Department of Physiological Chemistry, Biomedical Center, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany;
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Sarkadi
authors.affiliation: Department of Physiological Chemistry, Biomedical Center, Ludwig-Maximilians-University of Munich, 82152 Martinsried, Germany; International Max Planck Research School for Molecular and Cellular Life Sciences, 82152 Martinsried, Germany.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Braun
mesh_terms: D017353:Gene Deletion; D020868:Gene Silencing; D006570:Heterochromatin / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D012568:Schizosaccharomyces; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D006570:Heterochromatin; D009687:Nuclear Proteins; D029702:Schizosaccharomyces pombe Proteins; C475031:epe1 protein, S pombe
keywords: LEM; heterochromatin; lamin-associated proteins; nuclear periphery; perinuclear silencing; tethering