Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation

  1. Nicolás Peláez
  2. Arnau Gavalda-Miralles
  3. Bao Wang
  4. Heliodoro Tejedor Navarro
  5. Herman Gudjonson
  6. Ilaria Rebay
  7. Aaron R Dinner
  8. Aggelos K Katsaggelos
  9. Luis AN Amaral
  10. Richard W Carthew  Is a corresponding author
  1. Northwestern University, United States
  2. Universitat Rovira i Virgili, United States
  3. Howard Hughes Medical Institute, Northwestern University, United States
  4. University of Chicago, United States

Abstract

Yan is an ETS-domain transcription factor responsible for maintaining Drosophila eye cells in a multipotent state. Using a fluorescent reporter for Yan expression, we observed a biphasic distribution of Yan in multipotent cells. Transitions to various differentiated states occurred over the course of this dynamic process, suggesting that Yan expression level does not strongly determine cell potential. Consistent with this conclusion, perturbing Yan expression by varying gene dosage had no effect on cell fate transitions. However, we observed that as cells transited to differentiation, Yan expression became highly heterogeneous and this heterogeneity was transient. Signals received via the EGF Receptor were necessary for the transience in Yan noise since genetic loss caused sustained noise. Since these signals are essential for eye cells to differentiate, we suggest that dynamic heterogeneity of Yan is a necessary element of the transition process, and cell states are stabilized through noise reduction.

Article and author information

Author details

  1. Nicolás Peláez

    Department of Molecular Biosciences, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Arnau Gavalda-Miralles

    Department of Chemical Engineering, Universitat Rovira i Virgili, Tarragona, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Bao Wang

    Department Electrical Engineering and Computer Science, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Heliodoro Tejedor Navarro

    Department of Chemical and Biological Engineering, Howard Hughes Medical Institute, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Herman Gudjonson

    James Franck Institute, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ilaria Rebay

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Aaron R Dinner

    James Franck Institute, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Aggelos K Katsaggelos

    Department Electrical Engineering and Computer Science, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Luis AN Amaral

    Department of Chemical and Biological Engineering, Howard Hughes Medical Institute, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Richard W Carthew

    Department of Molecular Biosciences, Northwestern University, Evanston, United States
    For correspondence
    r-carthew@northwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Naama Barkai, Weizmann Institute of Science, Israel

Version history

  1. Received: May 22, 2015
  2. Accepted: November 18, 2015
  3. Accepted Manuscript published: November 19, 2015 (version 1)
  4. Version of Record published: January 13, 2016 (version 2)

Copyright

© 2015, Peláez 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

  • 4,427
    views
  • 776
    downloads
  • 38
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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. Nicolás Peláez
  2. Arnau Gavalda-Miralles
  3. Bao Wang
  4. Heliodoro Tejedor Navarro
  5. Herman Gudjonson
  6. Ilaria Rebay
  7. Aaron R Dinner
  8. Aggelos K Katsaggelos
  9. Luis AN Amaral
  10. Richard W Carthew
(2015)
Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation
eLife 4:e08924.
https://doi.org/10.7554/eLife.08924

Share this article

https://doi.org/10.7554/eLife.08924

Further reading

    1. Biochemistry and Chemical Biology
    2. Computational and Systems Biology
    Richard Sejour, Janet Leatherwood ... Bruce Futcher
    Research Article

    Previously, Tuller et al. found that the first 30–50 codons of the genes of yeast and other eukaryotes are slightly enriched for rare codons. They argued that this slowed translation, and was adaptive because it queued ribosomes to prevent collisions. Today, the translational speeds of different codons are known, and indeed rare codons are translated slowly. We re-examined this 5’ slow translation ‘ramp.’ We confirm that 5’ regions are slightly enriched for rare codons; in addition, they are depleted for downstream Start codons (which are fast), with both effects contributing to slow 5’ translation. However, we also find that the 5’ (and 3’) ends of yeast genes are poorly conserved in evolution, suggesting that they are unstable and turnover relatively rapidly. When a new 5’ end forms de novo, it is likely to include codons that would otherwise be rare. Because evolution has had a relatively short time to select against these codons, 5’ ends are typically slightly enriched for rare, slow codons. Opposite to the expectation of Tuller et al., we show by direct experiment that genes with slowly translated codons at the 5’ end are expressed relatively poorly, and that substituting faster synonymous codons improves expression. Direct experiment shows that slow codons do not prevent downstream ribosome collisions. Further informatic studies suggest that for natural genes, slow 5’ ends are correlated with poor gene expression, opposite to the expectation of Tuller et al. Thus, we conclude that slow 5’ translation is a ‘spandrel’--a non-adaptive consequence of something else, in this case, the turnover of 5’ ends in evolution, and it does not improve translation.

    1. Computational and Systems Biology
    Hedi Chen, Xiaoyu Fan ... Boxue Tian
    Research Article

    Accurate prediction of the structurally diverse complementarity determining region heavy chain 3 (CDR-H3) loop structure remains a primary and long-standing challenge for antibody modeling. Here, we present the H3-OPT toolkit for predicting the 3D structures of monoclonal antibodies and nanobodies. H3-OPT combines the strengths of AlphaFold2 with a pre-trained protein language model and provides a 2.24 Å average RMSD between predicted and experimentally determined CDR-H3 loops, thus outperforming other current computational methods in our non-redundant high-quality dataset. The model was validated by experimentally solving three structures of anti-VEGF nanobodies predicted by H3-OPT. We examined the potential applications of H3-OPT through analyzing antibody surface properties and antibody–antigen interactions. This structural prediction tool can be used to optimize antibody–antigen binding and engineer therapeutic antibodies with biophysical properties for specialized drug administration route.