Evolution of reduced co-activator dependence led to target expansion of a starvation response pathway

  1. Bin Z He  Is a corresponding author
  2. Xu Zhou
  3. Erin K O'Shea  Is a corresponding author
  1. Howard Hughes Medical Institute, Harvard University Faculty of Arts and Sciences Center for Systems Biology, United States
  2. Yale School of Medicine, United States

Abstract

Although combinatorial regulation is a common feature in gene regulatory networks, how it evolves and affects network structure and function is not well understood. In S. cerevisiae, the phosphate starvation (PHO) responsive transcription factors Pho4 and Pho2 are required for gene induction and survival during phosphate starvation. In the related human commensal C. glabrata, Pho4 is required but Pho2 is dispensable for survival in phosphate starvation and is only partially required for inducing PHO genes. Phylogenetic survey suggests that reduced dependence on Pho2 evolved in C. glabrata and closely related species. In S. cerevisiae, less Pho2-dependent Pho4 orthologs induce more genes. In C. glabrata, its Pho4 binds to more locations and induces three times as many genes as Pho4 in S. cerevisiae does. Our work shows how evolution of combinatorial regulation allows for rapid expansion of a gene regulatory network's targets, possibly extending its physiological functions.

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Author details

  1. Bin Z He

    Howard Hughes Medical Institute, Harvard University Faculty of Arts and Sciences Center for Systems Biology, Cambridge, United States
    For correspondence
    binhe@fas.harvard.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3072-6238
  2. Xu Zhou

    Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1692-6823
  3. Erin K O'Shea

    Howard Hughes Medical Institute, Harvard University Faculty of Arts and Sciences Center for Systems Biology, Cambridge, United States
    For correspondence
    osheae@hhmi.org
    Competing interests
    Erin K O'Shea, Chief Scientific Officer and a Vice President at the Howard Hughes Medical Institute, one of the three founding funders of eLife..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2649-1018

Funding

Howard Hughes Medical Institute

  • Bin Z He
  • Xu Zhou
  • Erin K O'Shea

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

Reviewing Editor

  1. Naama Barkai, Weizmann Institute of Science, Israel

Version history

  1. Received: January 15, 2017
  2. Accepted: April 29, 2017
  3. Accepted Manuscript published: May 9, 2017 (version 1)
  4. Version of Record published: May 26, 2017 (version 2)
  5. Version of Record updated: October 20, 2022 (version 3)

Copyright

© 2017, He 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. Bin Z He
  2. Xu Zhou
  3. Erin K O'Shea
(2017)
Evolution of reduced co-activator dependence led to target expansion of a starvation response pathway
eLife 6:e25157.
https://doi.org/10.7554/eLife.25157

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https://doi.org/10.7554/eLife.25157

Further reading

    1. Cell Biology
    2. Evolutionary Biology
    Jonathan E Phillips, Duojia Pan
    Research Advance

    The genomes of close unicellular relatives of animals encode orthologs of many genes that regulate animal development. However, little is known about the function of such genes in unicellular organisms or the evolutionary process by which these genes came to function in multicellular development. The Hippo pathway, which regulates cell proliferation and tissue size in animals, is present in some of the closest unicellular relatives of animals, including the amoeboid organism Capsaspora owczarzaki. We previously showed that the Capsaspora ortholog of the Hippo pathway nuclear effector Yorkie/YAP/TAZ (coYki) regulates actin dynamics and the three-dimensional morphology of Capsaspora cell aggregates, but is dispensable for cell proliferation control (Phillips et al., 2022). However, the function of upstream Hippo pathway components, and whether and how they regulate coYki in Capsaspora, remained unknown. Here, we analyze the function of the upstream Hippo pathway kinases coHpo and coWts in Capsaspora by generating mutant lines for each gene. Loss of either kinase results in increased nuclear localization of coYki, indicating an ancient, premetazoan origin of this Hippo pathway regulatory mechanism. Strikingly, we find that loss of either kinase causes a contractile cell behavior and increased density of cell packing within Capsaspora aggregates. We further show that this increased cell density is not due to differences in proliferation, but rather actomyosin-dependent changes in the multicellular architecture of aggregates. Given its well-established role in cell density-regulated proliferation in animals, the increased density of cell packing in coHpo and coWts mutants suggests a shared and possibly ancient and conserved function of the Hippo pathway in cell density control. Together, these results implicate cytoskeletal regulation but not proliferation as an ancestral function of the Hippo pathway kinase cascade and uncover a novel role for Hippo signaling in regulating cell density in a proliferation-independent manner.