1. Chromosomes and Gene Expression
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Progerin reduces LAP2α-telomere association in Hutchinson-Gilford progeria

  1. Alexandre Chojnowski
  2. Peh Fern Ong
  3. Esther SM Wong
  4. John SY Lim
  5. Rafidah A Mutalif
  6. Raju Navasankari
  7. Bamaprasad Dutta
  8. Henry Yang
  9. Yi Y Liow
  10. Siu K Sze
  11. Thomas Boudier
  12. Graham D Wright
  13. Alan Colman
  14. Brian Burke
  15. Colin L Stewart
  16. Oliver Dreesen  Is a corresponding author
  1. Institute of Medical Biology, Singapore
  2. Nanyang Technological University, Singapore
  3. National University of Singapore, Singapore
  4. IPAL UMI 2955, Singapore
Research Article
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Cite this article as: eLife 2015;4:e07759 doi: 10.7554/eLife.07759

Abstract

Hutchinson-Gilford progeria (HGPS) is a premature ageing syndrome caused by a mutation in LMNA, resulting in a truncated form of lamin A called progerin. Progerin triggers loss of the heterochromatic marker H3K27me3, and premature senescence, which is prevented by telomerase. However, the mechanism how progerin causes disease remains unclear. Here, we describe an inducible cellular system to model HGPS and find that LAP2α (lamina-associated polypeptide-α) interacts with lamin A, while its interaction with progerin is significantly reduced. Super-resolution microscopy revealed that over 50% of telomeres localize to the lamina and that LAP2α association with telomeres is impaired in HGPS. This impaired interaction is central to HGPS since increasing LAP2α levels rescues progerin-induced proliferation defects and loss of H3K27me3, whereas lowering LAP2 levels exacerbates progerin-induced defects. These findings provide novel insights into the pathophysiology underlying HGPS, and how the nuclear lamina regulates proliferation and chromatin organization.

Article and author information

Author details

  1. Alexandre Chojnowski

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  2. Peh Fern Ong

    Cellular Ageing, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  3. Esther SM Wong

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  4. John SY Lim

    Microscopy Unit, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  5. Rafidah A Mutalif

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  6. Raju Navasankari

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  7. Bamaprasad Dutta

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  8. Henry Yang

    Bioinformatics Core, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  9. Yi Y Liow

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  10. Siu K Sze

    School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  11. Thomas Boudier

    Bioinformatics Institute, IPAL UMI 2955, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  12. Graham D Wright

    Microscopy Unit, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  13. Alan Colman

    Stem Cell Disease Models, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  14. Brian Burke

    Nuclear Dynamics and Architecture, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  15. Colin L Stewart

    Developmental and Regenerative Biology, Institute of Medical Biology, Singapore, Singapore
    Competing interests
    The authors declare that no competing interests exist.
  16. Oliver Dreesen

    Cellular Ageing, Institute of Medical Biology, Singapore, Singapore
    For correspondence
    oliver.dreesen@imb.a-star.edu.sg
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (140960) of the Institute of Medical Biology, A*STAR, Singapore.

Reviewing Editor

  1. Karsten Weis, ETH Zürich, Switzerland

Publication history

  1. Received: March 27, 2015
  2. Accepted: August 23, 2015
  3. Accepted Manuscript published: August 27, 2015 (version 1)
  4. Version of Record published: September 11, 2015 (version 2)

Copyright

© 2015, Chojnowski et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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