SWI/SNF senses carbon starvation with a pH-sensitive low complexity sequence

  1. J Ignacio Gutierrez
  2. Gregory P Brittingham
  3. Yonca B Karadeniz
  4. Kathleen D Tran
  5. Arnob Dutta
  6. Alex S Holehouse
  7. Craig L Peterson
  8. Liam J Holt  Is a corresponding author
  1. Weill Cornell Medical College, United States
  2. New York University Langone Health, United States
  3. University of Massachusetts Medical School, United States
  4. University of Rhode Island, United States
  5. Washington University in St. Louis, United States

Abstract

It is increasingly appreciated that intracellular pH changes are important biological signals. This motivates the elucidation of molecular mechanisms of pH-sensing. We determined that a nucleocytoplasmic pH oscillation was required for the transcriptional response to carbon starvation in Saccharomyces cerevisiae. The SWI/SNF chromatin remodeling complex is a key mediator of this transcriptional response. A glutamine-rich low complexity domain (QLC) in the SNF5 subunit of this complex, and histidines within this sequence, were required for efficient transcriptional reprogramming. Furthermore, the SNF5 QLC mediated pH-dependent recruitment of SWI/SNF to an acidic transcription factor in a reconstituted nucleosome remodeling assay. Simulations showed that protonation of histidines within the SNF5 QLC lead to conformational expansion, providing a potential biophysical mechanism for regulation of these interactions. Together, our results indicate that that pH changes are a second messenger for transcriptional reprogramming during carbon starvation, and that the SNF5 QLC acts as a pH-sensor.

Data availability

Simulation code and details can be found at:https://github.com/holehouse-lab/supportingdata/tree/master/2021/Gutierrez_QLC_2021RNA-seq R-code can be found at:https://github.com/gbritt/SWI_SNF_pH_Sensor_RNASeqRNA-seq datasets are depositied at GEO accession number GSE174687https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE174687

The following data sets were generated

Article and author information

Author details

  1. J Ignacio Gutierrez

    Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9017-8384
  2. Gregory P Brittingham

    Institute for Systems Genetics, New York University Langone Health, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yonca B Karadeniz

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8299-551X
  4. Kathleen D Tran

    Department of Cell and Molecular Biology, University of Rhode Island, South Kingstown, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Arnob Dutta

    Department of Cell and Molecular Biology, University of Rhode Island, South Kingstown, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alex S Holehouse

    Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4155-5729
  7. Craig L Peterson

    Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Liam J Holt

    Institute for Systems Genetics, New York University Langone Health, New York, United States
    For correspondence
    Liam.Holt@nyulangone.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4002-0861

Funding

Becas Chile

  • J Ignacio Gutierrez

National Science Foundation (Graduate Research Fellows Program)

  • Gregory P Brittingham

Pershing Square Sohn Cancer Research Award

  • Liam J Holt

National Cancer Institute (R37 CA240765)

  • Liam J Holt

National Institute of General Medical Sciences (R01 GM132447)

  • Liam J Holt

American Cancer Society Cornelia T. Bailey Foundation Research Scholar Grant (RSG-19-073-01-TBE)

  • Liam J Holt

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

Reviewing Editor

  1. Alan G Hinnebusch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States

Version history

  1. Preprint posted: March 3, 2021 (view preprint)
  2. Received: May 19, 2021
  3. Accepted: February 6, 2022
  4. Accepted Manuscript published: February 7, 2022 (version 1)
  5. Version of Record published: March 2, 2022 (version 2)

Copyright

© 2022, Gutierrez 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. J Ignacio Gutierrez
  2. Gregory P Brittingham
  3. Yonca B Karadeniz
  4. Kathleen D Tran
  5. Arnob Dutta
  6. Alex S Holehouse
  7. Craig L Peterson
  8. Liam J Holt
(2022)
SWI/SNF senses carbon starvation with a pH-sensitive low complexity sequence
eLife 11:e70344.
https://doi.org/10.7554/eLife.70344

Share this article

https://doi.org/10.7554/eLife.70344

Further reading

    1. Biochemistry and Chemical Biology
    Chi-Ning Chuang, Hou-Cheng Liu ... Ting-Fang Wang
    Research Article

    Serine(S)/threonine(T)-glutamine(Q) cluster domains (SCDs), polyglutamine (polyQ) tracts and polyglutamine/asparagine (polyQ/N) tracts are Q-rich motifs found in many proteins. SCDs often are intrinsically disordered regions that mediate protein phosphorylation and protein-protein interactions. PolyQ and polyQ/N tracts are structurally flexible sequences that trigger protein aggregation. We report that due to their high percentages of STQ or STQN amino acid content, four SCDs and three prion-causing Q/N-rich motifs of yeast proteins possess autonomous protein expression-enhancing activities. Since these Q-rich motifs can endow proteins with structural and functional plasticity, we suggest that they represent useful toolkits for evolutionary novelty. Comparative Gene Ontology (GO) analyses of the near-complete proteomes of 26 representative model eukaryotes reveal that Q-rich motifs prevail in proteins involved in specialized biological processes, including Saccharomyces cerevisiae RNA-mediated transposition and pseudohyphal growth, Candida albicans filamentous growth, ciliate peptidyl-glutamic acid modification and microtubule-based movement, Tetrahymena thermophila xylan catabolism and meiosis, Dictyostelium discoideum development and sexual cycles, Plasmodium falciparum infection, and the nervous systems of Drosophila melanogaster, Mus musculus and Homo sapiens. We also show that Q-rich-motif proteins are expanded massively in 10 ciliates with reassigned TAAQ and TAGQ codons. Notably, the usage frequency of CAGQ is much lower in ciliates with reassigned TAAQ and TAGQ codons than in organisms with expanded and unstable Q runs (e.g. D. melanogaster and H. sapiens), indicating that the use of noncanonical stop codons in ciliates may have coevolved with codon usage biases to avoid triplet repeat disorders mediated by CAG/GTC replication slippage.

    1. Biochemistry and Chemical Biology
    2. Developmental Biology
    Sima Stroganov, Talia Harris ... Michal Neeman
    Research Article Updated

    Background:

    Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

    Methods:

    Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry.

    Results:

    We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1α levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation.

    Conclusions:

    This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR.

    Funding:

    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.