Precise let-7 expression levels balance organ regeneration against tumor suppression

  1. Linwei Wu
  2. Liem H Nguyen
  3. Kejin Zhou
  4. T Yvanka de Soysa
  5. Lin Li
  6. Jason B Miller
  7. Jianmin Tian
  8. Joseph Locker
  9. Shuyuan Zhang
  10. Gen Shinoda
  11. Marc T Seligson
  12. Lauren R Zeitels
  13. Asha Acharya
  14. Sam C Wang
  15. Joshua T Mendell
  16. Xiaoshun He
  17. Jinsuke Nishino
  18. Sean J Morrison
  19. Daniel J Siegwart
  20. George Q Daley
  21. Ng Shyh-Chang
  22. Hao Zhu  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Boston Children's Hospital and Dana Farber Cancer Institute, United States
  3. University of Pittsburg, United States
  4. The First Affiliated Hospital of Sun Yat-Sen University, China
  5. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
  6. Harvard Medical School, United States
  7. Children's Hospital and Dana Farber Cancer Institute, United States

Abstract

The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.

Article and author information

Author details

  1. Linwei Wu

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  2. Liem H Nguyen

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. Kejin Zhou

    Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  4. T Yvanka de Soysa

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Lin Li

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  6. Jason B Miller

    Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  7. Jianmin Tian

    Department of Pathology, University of Pittsburg, Pittsburg, United States
    Competing interests
    No competing interests declared.
  8. Joseph Locker

    Department of Pathology, University of Pittsburg, Pittsburg, United States
    Competing interests
    No competing interests declared.
  9. Shuyuan Zhang

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  10. Gen Shinoda

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  11. Marc T Seligson

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  12. Lauren R Zeitels

    Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  13. Asha Acharya

    Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  14. Sam C Wang

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  15. Joshua T Mendell

    Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  16. Xiaoshun He

    Organ Transplant Center, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
    Competing interests
    No competing interests declared.
  17. Jinsuke Nishino

    Children's Medical Center Research Institute at UT Southwestern, Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  18. Sean J Morrison

    Children's Medical Center Research Institute at UT Southwestern, Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    Sean J Morrison, Senior editor, eLife.
  19. Daniel J Siegwart

    Simmons Comprehensive Cancer Center, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  20. George Q Daley

    Children's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  21. Ng Shyh-Chang

    Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Children's Hospital and Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  22. Hao Zhu

    Children's Research Institute, Departments of Pediatrics and Internal Medicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    Hao.Zhu@utsouthwestern.edu
    Competing interests
    No competing interests declared.

Reviewing Editor

  1. Amy J Wagers, Harvard University, United States

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 (#2012-0143) of the University of Texas Southwestern Medical Center. All surgery was performed under isoflurane anesthesia with appropriate analgesia, and every effort was made to minimize suffering.

Version history

  1. Received: June 15, 2015
  2. Accepted: October 5, 2015
  3. Accepted Manuscript published: October 7, 2015 (version 1)
  4. Version of Record published: December 10, 2015 (version 2)

Copyright

© 2015, Wu 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.

Metrics

  • 3,128
    Page views
  • 907
    Downloads
  • 47
    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. Linwei Wu
  2. Liem H Nguyen
  3. Kejin Zhou
  4. T Yvanka de Soysa
  5. Lin Li
  6. Jason B Miller
  7. Jianmin Tian
  8. Joseph Locker
  9. Shuyuan Zhang
  10. Gen Shinoda
  11. Marc T Seligson
  12. Lauren R Zeitels
  13. Asha Acharya
  14. Sam C Wang
  15. Joshua T Mendell
  16. Xiaoshun He
  17. Jinsuke Nishino
  18. Sean J Morrison
  19. Daniel J Siegwart
  20. George Q Daley
  21. Ng Shyh-Chang
  22. Hao Zhu
(2015)
Precise let-7 expression levels balance organ regeneration against tumor suppression
eLife 4:e09431.
https://doi.org/10.7554/eLife.09431

Share this article

https://doi.org/10.7554/eLife.09431

Further reading

    1. Cell Biology
    Kazuki Hanaoka, Kensuke Nishikawa ... Kouichi Funato
    Research Article

    Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)–plasma membrane (PM) and ER–Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus–vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Monica Salinas-Pena, Elena Rebollo, Albert Jordan
    Research Article

    Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit characteristic distribution patterns in both interphase and mitosis. H1.2, H1.3, and H1.5 are universally enriched at the nuclear periphery in all cell lines analyzed and co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, with apparent variability among different cell lines. On the other hand, H1.4 and H1X are distributed throughout the nucleus, being H1X universally enriched in high-GC regions and abundant in the nucleoli. Interestingly, H1.4 and H1.0 show a more peripheral distribution in cell lines lacking H1.3 and H1.5. The differential distribution patterns of H1 suggest specific functionalities in organizing lamina-associated domains or nucleolar activity, which is further supported by a distinct response of H1X or phosphorylated H1.4 to the inhibition of ribosomal DNA transcription. Moreover, H1 variants depletion affects chromatin structure in a variant-specific manner. Concretely, H1.2 knock-down, either alone or combined, triggers a global chromatin decompaction. Overall, imaging has allowed us to distinguish H1 variants distribution beyond the segregation in two groups denoted by previous ChIP-Seq determinations. Our results support H1 variants heterogeneity and suggest that variant-specific functionality can be shared between different cell types.