A Non-stop identity complex (NIC) supervises enterocyte identity and protects from pre-mature aging

  1. Neta Erez
  2. Lena Israitel
  3. Eliya Bitman-Lotan
  4. Wing H Wong
  5. Gal Raz
  6. Dayanne V Cornelio-Parra
  7. Salwa Danial
  8. Na'ama Flint Brodsly
  9. Elena Belova
  10. Oksana Maksimenko
  11. Pavel Georgiev
  12. Todd Druley
  13. Ryan D Mohan PhD
  14. Amir Orian  Is a corresponding author
  1. Technion-Israel Institute of Technology, Israel
  2. Washington University, United States
  3. University of Missouri - Kansas City, United States
  4. Institute of Gene Biology Russian Academy of Sciences, Russian Federation

Abstract

A hallmark of aging is loss of differentiated cell identity. Aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus<strong>.</strong> Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.

Data availability

The following sequencing data were deposited: RNAseq and ATAC-seq data are available at NCBI through the Accession number PRJNA657899Link to the the proteomic data set is: The permanent URL to the dataset is: ftp://massive.ucsd.edu/MSV000082625. The data is also accessible from: ProteomeXChange accession: PXD010462 http://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD010462. MassIVE | Accession ID: MSV000082625 - ProteomeXchange | Accession ID: PXD010462.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Neta Erez

    Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Lena Israitel

    Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Eliya Bitman-Lotan

    Faculty fo Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  4. Wing H Wong

    Division of Pediatric Hematology and Oncology, Washington University, Saint-Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Gal Raz

    Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Dayanne V Cornelio-Parra

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Salwa Danial

    Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Na'ama Flint Brodsly

    Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Elena Belova

    Genetics, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  10. Oksana Maksimenko

    partment of the Control of Genetic Processes, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  11. Pavel Georgiev

    Genetics, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russian Federation
    Competing interests
    The authors declare that no competing interests exist.
  12. Todd Druley

    Division of Pediatric Hematology and Oncology, Washington University, Saint-Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Ryan D Mohan PhD

    School of Biological and Chemical Sciences, University of Missouri - Kansas City, Kansas City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7624-4605
  14. Amir Orian

    Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
    For correspondence
    mdoryan@tx.technion.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8521-1661

Funding

NIH NIGMS (5R35GM118068)

  • Ryan D Mohan PhD

CDI (MC-II-2014-363)

  • Todd Druley

Russian Science Foundation (19-74-30026)

  • Pavel Georgiev

Israel Academy of Sciences and Humanities (719/15)

  • Amir Orian

Israel Academy of Sciences and Humanities (318/20)

  • Amir Orian

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Pankaj Kapahi, Buck Institute for Research on Aging, United States

Publication history

  1. Received: August 21, 2020
  2. Accepted: February 17, 2021
  3. Accepted Manuscript published: February 25, 2021 (version 1)
  4. Version of Record published: March 5, 2021 (version 2)

Copyright

© 2021, Erez 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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  1. Neta Erez
  2. Lena Israitel
  3. Eliya Bitman-Lotan
  4. Wing H Wong
  5. Gal Raz
  6. Dayanne V Cornelio-Parra
  7. Salwa Danial
  8. Na'ama Flint Brodsly
  9. Elena Belova
  10. Oksana Maksimenko
  11. Pavel Georgiev
  12. Todd Druley
  13. Ryan D Mohan PhD
  14. Amir Orian
(2021)
A Non-stop identity complex (NIC) supervises enterocyte identity and protects from pre-mature aging
eLife 10:e62312.
https://doi.org/10.7554/eLife.62312

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