Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail

  1. Brandon R Lowe
  2. Rajesh K Yadav
  3. Ryan A Henry
  4. Patrick Schreiner
  5. Atsushi Matsuda
  6. Alfonso G Fernandez
  7. David Finkelstein
  8. Margaret Campbell
  9. Satish Kallappagoudar
  10. Carolyn M Jablonowski
  11. Andrew J Andrews
  12. Yasushi Hiraoka
  13. Janet F Partridge  Is a corresponding author
  1. St Jude Children's Research Hospital, United States
  2. Fox Chase Cancer Center, United States
  3. National Institute of Information and Communications Technology, Japan
  4. Osaka University, Japan

Abstract

Sequencing of cancer genomes has identified recurrent somatic mutations in histones, termed oncohistones, which are frequently poorly understood. Previously we showed that fission yeast expressing only the H3.3G34R mutant identified in aggressive pediatric glioma had reduced H3K36 trimethylation and acetylation, increased genomic instability and replicative stress, and defective homology-dependent DNA damage repair (Yadav et al., 2017). Here we show that surprisingly distinct phenotypes result from G34V (also in glioma) and G34W (giant cell tumors of bone) mutations, differentially affecting H3K36 modifications, subtelomeric silencing, genomic stability, sensitivity to irradiation, alkylating agents, hydroxyurea and influencing DNA repair. In cancer, only one of thirty alleles encoding H3 is mutated. Whilst co-expression of wild-type H3 rescues most G34 mutant phenotypes, G34R causes dominant hydroxyurea sensitivity and homologous recombination defects, and dominant subtelomeric silencing. Together, these studies demonstrate the complexity associated with different substitutions at even a single residue in H3 and highlight the utility of genetically tractable systems for their analysis.

Data availability

RNAseq data have been deposited in GEO under accession code GSE162572.

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

Article and author information

Author details

  1. Brandon R Lowe

    Department of Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rajesh K Yadav

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ryan A Henry

    Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Patrick Schreiner

    Center for Applied Bioinformatics, Dept. of Bioinformatics, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5391-2642
  5. Atsushi Matsuda

    Advanced ICT Research Institute, National Institute of Information and Communications Technology, Kobe, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0510-213X
  6. Alfonso G Fernandez

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. David Finkelstein

    Computational Biology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Margaret Campbell

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Satish Kallappagoudar

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Carolyn M Jablonowski

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Andrew J Andrews

    Cancer Biology, Fox Chase Cancer Center, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Yasushi Hiraoka

    Graduate School of Frontier Biosciences, Osaka University, Suita, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9407-8228
  13. Janet F Partridge

    Pathology, St Jude Children's Research Hospital, Memphis, United States
    For correspondence
    janet.partridge@stjude.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1102-6305

Funding

St. Baldrick's Foundation (Research grant with generous support from the Henry Cermak fund for Pediatric Cancer Research.)

  • Janet F Partridge

National Cancer Institute (Cancer Center support grant (NCI CCSG 2 P30 CA21765))

  • Rajesh K Yadav
  • Janet F Partridge

American Lebanese Syrian Associated Charities

  • Brandon R Lowe
  • Rajesh K Yadav
  • Patrick Schreiner
  • Alfonso G Fernandez
  • David Finkelstein
  • Margaret Campbell
  • Satish Kallappagoudar
  • Carolyn M Jablonowski
  • Janet F Partridge

National Institutes of Health (NIH GM102503)

  • Andrew J Andrews

Fox Chase Cancer Center (Board of Associates Fellowship)

  • Ryan A Henry

Japan Society for the Promotion of Science (Kakheni grant JP19H03202 and JP20H05894)

  • Atsushi Matsuda

Japan Society for the Promotion of Science (Kakheni grants JP18H05533 and JP20H00454)

  • Yasushi Hiraoka

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

Reviewing Editor

  1. Jerry L Workman, Stowers Institute for Medical Research, United States

Version history

  1. Received: December 2, 2020
  2. Accepted: January 30, 2021
  3. Accepted Manuscript published: February 1, 2021 (version 1)
  4. Version of Record published: February 9, 2021 (version 2)

Copyright

© 2021, Lowe 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

  • 1,638
    Page views
  • 290
    Downloads
  • 18
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Brandon R Lowe
  2. Rajesh K Yadav
  3. Ryan A Henry
  4. Patrick Schreiner
  5. Atsushi Matsuda
  6. Alfonso G Fernandez
  7. David Finkelstein
  8. Margaret Campbell
  9. Satish Kallappagoudar
  10. Carolyn M Jablonowski
  11. Andrew J Andrews
  12. Yasushi Hiraoka
  13. Janet F Partridge
(2021)
Surprising phenotypic diversity of cancer-associated mutations of Gly 34 in the histone H3 tail
eLife 10:e65369.
https://doi.org/10.7554/eLife.65369

Share this article

https://doi.org/10.7554/eLife.65369

Further reading

    1. Chromosomes and Gene Expression
    Rachel A Johnston, Katherine A Aracena ... Jenny Tung
    Research Advance

    Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures—one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Carolline Ascenção, Jennie R Sims ... Marcus B Smolka
    Research Article

    Meiotic sex chromosome inactivation (MSCI) is a critical feature of meiotic prophase I progression in males. While the ATR kinase and its activator TOPBP1 are key drivers of MSCI within the specialized sex body (SB) domain of the nucleus, how they promote silencing remains unclear given their multifaceted meiotic functions that also include DNA repair, chromosome synapsis, and SB formation. Here we report a novel mutant mouse harboring mutations in the TOPBP1-BRCT5 domain. Topbp1B5/B5 males are infertile, with impaired MSCI despite displaying grossly normal events of early prophase I, including synapsis and SB formation. Specific ATR-dependent events are disrupted, including phosphorylation and localization of the RNA:DNA helicase Senataxin. Topbp1B5/B5 spermatocytes initiate, but cannot maintain ongoing, MSCI. These findings reveal a non-canonical role for the ATR-TOPBP1 signaling axis in MSCI dynamics at advanced stages in pachynema and establish the first mouse mutant that separates ATR signaling and MSCI from SB formation.