Nucleoplasmic Lamin A/C and Polycomb group of proteins: An evolutionarily conserved interplay

ABSTRACT Nuclear lamins are the main components of the nuclear lamina at the nuclear periphery, providing mechanical support to the nucleus. However, recent findings suggest that lamins also reside in the nuclear interior, as a distinct and dynamic pool with critical roles in transcriptional regulation. In our work we found a functional and evolutionary conserved crosstalk between Lamin A/C and the Polycomb group (PcG) of proteins, this being required for the maintenance of the PcG repressive functions. Indeed, Lamin A/C knock-down causes PcG foci dispersion and defects in PcG-mediated higher order structures, thereby leading to impaired PcG mediated transcriptional repression. By using ad-hoc algorithms for image analysis and PLA approaches we hereby show that PcG proteins are preferentially located in the nuclear interior where they interact with nucleoplasmic Lamin A/C. Taken together, our findings suggest that nuclear components, such as Lamin A/C, functionally interact with epigenetic factors to ensure the correct transcriptional program maintenance.

[1]  A. von Haeseler,et al.  A-type lamins bind both hetero- and euchromatin, the latter being regulated by lamina-associated polypeptide 2 alpha , 2016, Genome research.

[2]  Patrick Schorderet,et al.  Chromatin topology is coupled to Polycomb group protein subnuclear organization , 2016, Nature Communications.

[3]  Leonid A. Mirny,et al.  Super-resolution imaging reveals distinct chromatin folding for different epigenetic states , 2015, Nature.

[4]  E. Cesarini,et al.  Lamin A/C sustains PcG protein architecture, maintaining transcriptional repression at target genes , 2015, The Journal of cell biology.

[5]  C. Lanzuolo,et al.  Into the chromatin world: Role of nuclear architecture in epigenome regulation , 2015 .

[6]  Louise S. Matheson,et al.  Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome , 2015, Nature Genetics.

[7]  R. Foisner,et al.  Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation. , 2015, Annual review of biochemistry.

[8]  R. Foisner,et al.  Lamina-associated polypeptide (LAP)2α and nucleoplasmic lamins in adult stem cell regulation and disease☆ , 2014, Seminars in cell & developmental biology.

[9]  Giacomo Cavalli,et al.  Polycomb silencing: from linear chromatin domains to 3D chromosome folding. , 2014, Current opinion in genetics & development.

[10]  P. Collas,et al.  Closing the (nuclear) envelope on the genome: How nuclear lamins interact with promoters and modulate gene expression , 2014, BioEssays : news and reviews in molecular, cellular and developmental biology.

[11]  Dennis E. Discher,et al.  Nuclear Lamin-A Scales with Tissue Stiffness and Enhances Matrix-Directed Differentiation , 2013, Science.

[12]  E. Delbarre,et al.  Lamin A/C-promoter interactions specify chromatin state–dependent transcription outcomes , 2013, Genome Research.

[13]  W. Bickmore,et al.  Single-Cell Dynamics of Genome-Nuclear Lamina Interactions , 2013, Cell.

[14]  R. Paro,et al.  PcG-Mediated Higher-Order Chromatin Structures Modulate Replication Programs at the Drosophila BX-C , 2013, PLoS genetics.

[15]  Rachel Patton McCord,et al.  Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome , 2013, Genome research.

[16]  Manolis Kellis,et al.  Constitutive nuclear lamina–genome interactions are highly conserved and associated with A/T-rich sequence , 2013, Genome research.

[17]  V. Orlando,et al.  Memories from the polycomb group proteins. , 2012, Annual review of genetics.

[18]  L. Morey,et al.  Polycomb in stem cells: PRC1 branches out. , 2012, Cell stem cell.

[19]  C. Lanzuolo.  Epigenetic Alterations in Muscular Disorders , 2012, Comparative and functional genomics.

[20]  V. Orlando,et al.  Concerted epigenetic signatures inheritance at PcG targets through replication , 2012, Cell cycle.

[21]  Giacomo Cavalli,et al.  Progressive Polycomb Assembly on H3K27me3 Compartments Generates Polycomb Bodies with Developmentally Regulated Motion , 2012, PLoS genetics.

[22]  U. Aebi,et al.  Lamin A and lamin C form homodimers and coexist in higher complex forms both in the nucleoplasmic fraction and in the lamina of cultured human cells , 2011, Nucleus.

[23]  T. Misteli,et al.  Post-natal myogenic and adipogenic developmental , 2011, Nucleus.

[24]  B. van Steensel,et al.  Interactions among Polycomb Domains Are Guided by Chromosome Architecture , 2011, PLoS genetics.

[25]  Benjamin Leblanc,et al.  Polycomb-Dependent Regulatory Contacts between Distant Hox Loci in Drosophila , 2011, Cell.

[26]  D. Reinberg,et al.  The Polycomb complex PRC2 and its mark in life , 2011, Nature.

[27]  B. van Steensel,et al.  Genome-nuclear lamina interactions and gene regulation. , 2010, Current opinion in cell biology.

[28]  C. Stewart,et al.  Loss of LAP2α Delays Satellite Cell Differentiation and Affects Postnatal Fiber‐Type Determination , 2010, Stem cells.

[29]  C. Stewart,et al.  Lamina-Associated Polypeptide 2&agr; Loss Impairs Heart Function and Stress Response in Mice , 2010, Circulation research.

[30]  R. Foisner,et al.  Lamin complexes in the nuclear interior control progenitor cell proliferation and tissue homeostasis , 2009, Cell cycle.

[31]  R. Foisner,et al.  Prelamin A is involved in early steps of muscle differentiation. , 2008, Experimental cell research.

[32]  C. Stewart,et al.  Loss of nucleoplasmic LAP2α–lamin A complexes causes erythroid and epidermal progenitor hyperproliferation , 2008, Nature Cell Biology.

[33]  Chiara Lanzuolo,et al.  Polycomb response elements mediate the formation of chromosome higher-order structures in the bithorax complex , 2007, Nature Cell Biology.

[34]  M. Fornerod,et al.  Characterization of the Drosophila melanogaster genome at the nuclear lamina , 2006, Nature Genetics.

[35]  R. Trembath,et al.  SUN1 Interacts with Nuclear Lamin A and Cytoplasmic Nesprins To Provide a Physical Connection between the Nuclear Lamina and the Cytoskeleton , 2006, Molecular and Cellular Biology.

[36]  E. Markiewicz,et al.  Remodelling of the nuclear lamina and nucleoskeleton is required for skeletal muscle differentiation in vitro , 2005, Journal of Cell Science.

[37]  G. Lyons,et al.  The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. , 2004, Genes & development.

[38]  H. Worman,et al.  Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy. , 2001, Journal of cell science.

[39]  R. Goldman,et al.  Nuclear Lamins a and B1: Different Pathways of Assembly during Nuclear Envelope Formation in Living Cells , 2000 .

[40]  R. Foisner,et al.  Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins. , 2000, Journal of cell science.

[41]  R. Foisner,et al.  Review: lamina-associated polypeptide 2 isoforms and related proteins in cell cycle-dependent nuclear structure dynamics. , 2000, Journal of structural biology.

[42]  A. Sasseville,et al.  Lamin proteins form an internal nucleoskeleton as well as a peripheral lamina in human cells. , 1995, Journal of cell science.

[43]  C. Stewart,et al.  Teratocarcinoma stem cells and early mouse embryos contain only a single major lamin polypeptide closely resembling lamin B , 1987, Cell.

[44]  C. Lehner,et al.  Biogenesis of the nuclear lamina: in vivo synthesis and processing of nuclear protein precursors. , 1986, Proceedings of the National Academy of Sciences of the United States of America.