1. Cell Biology
  2. Chromosomes and Gene Expression

Chromosome mis-segregation and cytokinesis failure in trisomic human cells

  1. Joshua M Nicholson
  2. Joana C Macedo
  3. Aaron J Mattingly
  4. Darawalee Wangsa
  5. Jordi Camps
  6. Vera Lima
  7. Ana M Gomes
  8. Sofia Dória
  9. Thomas Ried
  10. Elsa Logarinho
  11. Daniela Cimini  Is a corresponding author
  1. Virginia Tech, United States
  2. Universidade do Porto, Portugal
  3. University of California, San Francisco, United States
  4. National Institutes of Health, United States
  5. Institut D'Investigacions Biomèdiques August Pi i Sunyer, Spain
https://doi.org/10.7554/eLife.05068
Share this article
Cite this article
  1. Joshua M Nicholson
  2. Joana C Macedo
  3. Aaron J Mattingly
  4. Darawalee Wangsa
  5. Jordi Camps
  6. Vera Lima
  7. Ana M Gomes
  8. Sofia Dória
  9. Thomas Ried
  10. Elsa Logarinho
  11. Daniela Cimini
(2015)
Chromosome mis-segregation and cytokinesis failure in trisomic human cells
eLife 4:e05068.
https://doi.org/10.7554/eLife.05068
  2. Download BibTeX
  3. Download .RIS

Abstract

Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n=46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is both required and sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome.

Article and author information

Author details

  1. Joshua M Nicholson

    Department of Biological Sciences, Virginia Tech, Blacksburg, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Joana C Macedo

    Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  3. Aaron J Mattingly

    Cell and Tissue Biology, School of Dentistry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Darawalee Wangsa

    Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jordi Camps

    Gastrointestinal and Pancreatic Oncology Group, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut D'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.

  6. Vera Lima

    Department of Genetics, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  7. Ana M Gomes

    Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  8. Sofia Dória

    Department of Genetics, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  9. Thomas Ried

    Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Elsa Logarinho

    Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
    Competing interests
    The authors declare that no competing interests exist.

  11. Daniela Cimini

    Department of Biological Sciences, Virginia Tech, Blacksburg, United States
    For correspondence
    cimini@vt.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: The study acknowledged the ethics guidelines under national rules and accordingly to the principles of the Declaration of Helsinki, and was approved by the Ethics Committee of Hospital de S. Jo�o-Porto (dispatch 14 Nov 2012) (approval number 237/2012). Informed consent forms with detailed information were provided to all patients. The study did not imply collection of extra material from the healthy donor females (only surplus cells/tissues were used); the study didn't bring any direct benefits to the volunteers; there were no risks or costs for the volunteers; there was no access to patient clinical data (samples were obtained in anonymous form from the Hospital Genetics Department); participation was volunteer and free to be interrupted at any moment; there are no ethical impacts predicted; there will be no commercial interests.

Reviewing Editor

  1. Jon Pines, The Gurdon Institute, United Kingdom

Publication history

  1. Received: October 7, 2014
  2. Accepted: May 1, 2015
  3. Accepted Manuscript published: May 5, 2015 (version 1)
  4. Version of Record published: May 27, 2015 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 12,305
    Page views
  • 926
    Downloads
  • 66
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Joshua M Nicholson
  2. Joana C Macedo
  3. Aaron J Mattingly
  4. Darawalee Wangsa
  5. Jordi Camps
  6. Vera Lima
  7. Ana M Gomes
  8. Sofia Dória
  9. Thomas Ried
  10. Elsa Logarinho
  11. Daniela Cimini
(2015)
Chromosome mis-segregation and cytokinesis failure in trisomic human cells
eLife 4:e05068.
https://doi.org/10.7554/eLife.05068

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma

    Kimberly J Morgan, Karen Doggett ... Joan K Heath
    Research Article Updated

    The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly, and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional programme that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks krasG12V-driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the 10 components of the NUP107–160 subcomplex, which includes AHCTF1, is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.

    1. Cell Biology
    2. Immunology and Inflammation

    Spatially resolved transcriptomics reveals pro-inflammatory fibroblast involved in lymphocyte recruitment through CXCL8 and CXCL10

    Ana J Caetano, Yushi Redhead ... Paul T Sharpe
    Research Article Updated

    The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.

    1. Cell Biology
    2. Developmental Biology

    Peroxiredoxin 5 regulates osteogenic differentiation through interaction with hnRNPK during bone regeneration

    Eunjin Cho, Xiangguo Che ... Tae-Hoon Lee
    Research Article

    Peroxiredoxin 5 (Prdx5) is involved in pathophysiological regulation via the stress-induced cellular response. However, its function in the bone remains largely unknown. Here, we show that Prdx5 is involved in osteoclast and osteoblast differentiation, resulting in osteoporotic phenotypes in Prdx5 knockout (Prdx5Ko) male mice. To investigate the function of Prdx5 in the bone, osteoblasts were analyzed through immunoprecipitation (IP) and liquid chromatography combined with tandem mass spectrometry (LC–MS/MS) methods, while osteoclasts were analyzed through RNA-sequencing. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as a potential binding partner of Prdx5 during osteoblast differentiation in vitro. Prdx5 acts as a negative regulator of hnRNPK-mediated osteocalcin (Bglap) expression. In addition, transcriptomic analysis revealed that in vitro differentiated osteoclasts from the bone marrow-derived macrophages of Prdx5Ko mice showed enhanced expression of several osteoclast-related genes. These findings indicate that Prdx5 might contribute to the maintenance of bone homeostasis by regulating osteoblast differentiation. This study proposes a new function of Prdx5 in bone remodeling that may be used in developing therapeutic strategies for bone diseases.