title: Cytoskeletal tension induces the polarized architecture of the nucleus.
abstract: The nuclear lamina is a thin filamentous meshwork that provides mechanical support to the nucleus and regulates essential cellular processes such as DNA replication, chromatin organization, cell division, and differentiation. Isolated horizontal imaging using fluorescence and electron microscopy has long suggested that the nuclear lamina is composed of structurally different A-type and B-type lamin proteins and nuclear lamin-associated membrane proteins that together form a thin layer that is spatially isotropic with no apparent difference in molecular content or density between the top and bottom of the nucleus. Chromosomes are condensed differently along the radial direction from the periphery of the nucleus to the nuclear center; therefore, chromatin accessibility for gene expression is different along the nuclear radius. However, 3D confocal reconstruction reveals instead that major lamin protein lamin A/C forms an apically polarized Frisbee-like dome structure in the nucleus of adherent cells. Here we show that both A-type lamins and transcriptionally active chromatins are vertically polarized by the tension exercised by the perinuclear actin cap (or actin cap) that is composed of highly contractile actomyosin fibers organized at the apical surface of the nucleus. Mechanical coupling between actin cap and lamina through LINC (linkers of nucleoskeleton and cytoskeleton) protein complexes induces an apical distribution of transcription-active subnucleolar compartments and epigenetic markers of transcription-active genes. This study reveals that intranuclear structures, such as nuclear lamina and chromosomal architecture, are apically polarized through the extranuclear perinuclear actin cap in a wide range of somatic adherent cells.
authors.affiliation: Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA. Electronic address: kim.donghwee@jhu.edu.
authors.forename: Dong-Hwee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Johns Hopkins Physical Sciences - Oncology Center, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218, USA; Department of Pathology and Oncology and Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. Electronic address: wirtz@jhu.edu.
authors.forename: Denis
authors.initials: D
authors.lastname: Wirtz
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002875:Chromosomes; D003599:Cytoskeleton / Q000502:physiology*; D006801:Humans; D034882:Lamins / Q000378:metabolism; D051379:Mice
chemical_list: D034882:Lamins
keywords: Actin cap; Cell mechanics; Epigenetics; Lamin A/C; Nuclear lamina; Nuclear organization