Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

  1. Anthony S Findley
  2. Alan Monziani
  3. Allison L Richards
  4. Katherine Rhodes
  5. Michelle C Ward
  6. Cynthia A Kalita
  7. Adnan Alazizi
  8. Ali Pazokitoroudi
  9. Sriram Sankararaman
  10. Xiaoquan Wen
  11. David E Lanfear
  12. Roger Pique-Regi  Is a corresponding author
  13. Yoav Gilad  Is a corresponding author
  14. Francesca Luca  Is a corresponding author
  1. Wayne State University, United States
  2. University of Chicago, United States
  3. UCLA, United States
  4. University of Michigan, United States
  5. Henry Ford Hospital, United States

Abstract

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing, and were highly variable across contexts. For thousands of genes, we identified variable allelic expression across contexts and characterized different types of gene-environment interactions, many of which are associated with complex traits. Promoter functional and evolutionary features distinguished genes with elevated allelic imbalance mean and variance. On average half of the genes with dynamic regulatory interactions were missed by large eQTL mapping studies, indicating the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

Data availability

Sequencing files have been uploaded to the Sequence Read Archive (SRA) under Bioproject PRJNA694697

The following data sets were generated

Article and author information

Author details

  1. Anthony S Findley

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9922-3076
  2. Alan Monziani

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Allison L Richards

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Katherine Rhodes

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michelle C Ward

    Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1485-320X
  6. Cynthia A Kalita

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Adnan Alazizi

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ali Pazokitoroudi

    Department of Computer Science,, UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sriram Sankararaman

    Department of Computer Science,, UCLA, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaoquan Wen

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. David E Lanfear

    Center for Individualized and Genomic Medicine Research, Henry Ford Hospital, Detroit, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Roger Pique-Regi

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    For correspondence
    rpique@wayne.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1262-2275
  13. Yoav Gilad

    Department of Medicine, University of Chicago, Chicago, United States
    For correspondence
    gilad@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8284-8926
  14. Francesca Luca

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States
    For correspondence
    fluca@wayne.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8252-9052

Funding

National Institute of General Medical Sciences (R01GM109215)

  • Roger Pique-Regi
  • Francesca Luca

National Institute of General Medical Sciences (R35GM131726)

  • Yoav Gilad

National Institute of General Medical Sciences (F30GM131580)

  • Anthony S Findley

National Institute of General Medical Sciences (R35GM125055)

  • Sriram Sankararaman

National Science Foundation (III-1705121)

  • Ali Pazokitoroudi
  • Sriram Sankararaman

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

Reviewing Editor

  1. Stephen CJ Parker, University of Michigan, United States

Publication history

  1. Received: February 1, 2021
  2. Accepted: May 13, 2021
  3. Accepted Manuscript published: May 14, 2021 (version 1)
  4. Version of Record published: July 1, 2021 (version 2)

Copyright

© 2021, Findley 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

  • 2,828
    Page views
  • 358
    Downloads
  • 12
    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. Anthony S Findley
  2. Alan Monziani
  3. Allison L Richards
  4. Katherine Rhodes
  5. Michelle C Ward
  6. Cynthia A Kalita
  7. Adnan Alazizi
  8. Ali Pazokitoroudi
  9. Sriram Sankararaman
  10. Xiaoquan Wen
  11. David E Lanfear
  12. Roger Pique-Regi
  13. Yoav Gilad
  14. Francesca Luca
(2021)
Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions
eLife 10:e67077.
https://doi.org/10.7554/eLife.67077

Further reading

    1. Chromosomes and Gene Expression
    2. Immunology and Inflammation
    Suhas Sureshchandra, Brianna M Doratt ... Ilhem Messaoudi
    Research Article Updated

    Maternal pre-pregnancy (pregravid) obesity is associated with adverse outcomes for both mother and offspring. Amongst the complications for the offspring is increased susceptibility and severity of neonatal infections necessitating admission to the intensive care unit, notably bacterial sepsis and enterocolitis. Previous studies have reported aberrant responses to LPS and polyclonal stimulation by umbilical cord blood monocytes that were mediated by alterations in the epigenome. In this study, we show that pregravid obesity dysregulates umbilical cord blood monocyte responses to bacterial and viral pathogens. Specifically, interferon-stimulated gene expression and inflammatory responses to respiratory syncytial virus (RSV) and E. coli were significantly dampened, respectively . Although upstream signaling events were comparable, translocation of the key transcription factor NF-κB and chromatin accessibility at pro-inflammatory gene promoters following TLR stimulation was significantly attenuated. Using a rhesus macaque model of western style diet-induced obesity, we further demonstrate that this defect is detected in fetal peripheral monocytes and tissue-resident macrophages during gestation. Collectively, these data indicate that maternal obesity alters metabolic, signaling, and epigenetic profiles of fetal monocytes leading to a state of immune paralysis during late gestation and at birth.

    1. Chromosomes and Gene Expression
    2. Plant Biology
    Myeongjune Jeon, Goowon Jeong ... Ilha Lee
    Research Article

    To synchronize flowering time with spring, many plants undergo vernalization, a floral-promotion process triggered by exposure to long-term winter cold. In Arabidopsis thaliana, this is achieved through cold-mediated epigenetic silencing of the floral repressor, FLOWERING LOCUS C (FLC). COOLAIR, a cold-induced antisense RNA transcribed from the FLC locus, has been proposed to facilitate FLC silencing. Here, we show that C-repeat (CRT)/dehydration-responsive elements (DREs) at the 3′-end of FLC and CRT/DRE-binding factors (CBFs) are required for cold-mediated expression of COOLAIR. CBFs bind to CRT/DREs at the 3′-end of FLC, both in vitro and in vivo, and CBF levels increase gradually during vernalization. Cold-induced COOLAIR expression is severely impaired in cbfs mutants in which all CBF genes are knocked-out. Conversely, CBF-overexpressing plants show increased COOLAIR levels even at warm temperatures. We show that COOLAIR is induced by CBFs during early stages of vernalization but COOLAIR levels decrease in later phases as FLC chromatin transitions to an inactive state to which CBFs can no longer bind. We also demonstrate that cbfs and FLCΔCOOLAIR mutants exhibit a normal vernalization response despite their inability to activate COOLAIR expression during cold, revealing that COOLAIR is not required for the vernalization process.