1. Chromosomes and Gene Expression
Download icon

A promoter interaction map for cardiovascular disease genetics

  1. Lindsey E Montefiori  Is a corresponding author
  2. Debora R Sobreira
  3. Noboru J Sakabe
  4. Ivy Aneas
  5. Amelia C Joslin
  6. Grace T Hansen
  7. Grazyna Bozek
  8. Ivan P Moskowitz
  9. Elizabeth M McNally
  10. Marcelo A Nóbrega  Is a corresponding author
  1. University of Chicago, United States
  2. Northwestern University, United States
Tools and Resources
  • Cited 56
  • Views 7,687
  • Annotations
Cite this article as: eLife 2018;7:e35788 doi: 10.7554/eLife.35788

Abstract

Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), however most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1,999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.

Data availability

Raw and processed sequencing data are provided at ArrayExpress through accession numbers E-MTAB-6014 (Hi-C) and E-MTAB-6013 (RNA-seq).

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

Article and author information

Author details

  1. Lindsey E Montefiori

    Department of Human Genetics, University of Chicago, Chicago, United States
    For correspondence
    lem@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2342-6349
  2. Debora R Sobreira

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Noboru J Sakabe

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ivy Aneas

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

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Grace T Hansen

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Grazyna Bozek

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ivan P Moskowitz

    Department of Human Genetics, 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:" 0000-0003-0014-4963
  9. Elizabeth M McNally

    Center for Genetic Medicine, Northwestern University, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Marcelo A Nóbrega

    Department of Human Genetics, University of Chicago, Chicago, United States
    For correspondence
    nobrega@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0451-7846

Funding

National Institutes of Health (HL123857)

  • Marcelo A Nóbrega

National Institutes of Health (HL119967)

  • Marcelo A Nóbrega

National Institutes of Health (HL118758)

  • Marcelo A Nóbrega

National Institutes of Health (HL128075)

  • Elizabeth M McNally
  • Marcelo A Nóbrega

National Institutes of Health (T32GMOO7197)

  • Lindsey E Montefiori

American Heart Association (17PRE33410726)

  • Lindsey E Montefiori

National Institutes of Health (HL137307-01)

  • Lindsey E Montefiori

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

Reviewing Editor

  1. Job Dekker, University of Massachusetts Medical School, United States

Publication history

  1. Received: February 20, 2018
  2. Accepted: June 21, 2018
  3. Accepted Manuscript published: July 10, 2018 (version 1)
  4. Version of Record published: July 19, 2018 (version 2)

Copyright

© 2018, Montefiori 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

  • 7,687
    Page views
  • 994
    Downloads
  • 56
    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)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    2. Microbiology and Infectious Disease
    Michele Felletti et al.
    Research Article

    The ability to regulate DNA replication initiation in response to changing nutrient conditions is an important feature of most cell types. In bacteria, DNA replication is triggered by the initiator protein DnaA, which has long been suggested to respond to nutritional changes; nevertheless, the underlying mechanisms remain poorly understood. Here, we report a novel mechanism that adjusts DnaA synthesis in response to nutrient availability in Caulobacter crescentus. By performing a detailed biochemical and genetic analysis of the dnaA mRNA, we identified a sequence downstream of the dnaA start codon that inhibits DnaA translation elongation upon carbon exhaustion. Our data show that the corresponding peptide sequence, but not the mRNA secondary structure or the codon choice, is critical for this response, suggesting that specific amino acids in the growing DnaA nascent chain tune translational efficiency. Our study provides new insights into DnaA regulation and highlights the importance of translation elongation as a regulatory target. We propose that translation regulation by nascent chain sequences, like the one described, might constitute a general strategy for modulating the synthesis rate of specific proteins under changing conditions.

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    Benoit Roch et al.
    Research Article

    We developed a Xrcc4M61R separation of function mouse line to overcome the embryonic lethality of Xrcc4 deficient mice. XRCC4M61R protein does not interact with Xlf, thus obliterating XRCC4-Xlf filament formation while preserving the ability to stabilize DNA Ligase IV. X4M61R mice, which are DNA repair deficient, phenocopy the Nhej1-/- (known as Xlf -/-) setting with a minor impact on the development of the adaptive immune system. The core NHEJ DNA repair factor XRCC4 is therefore not mandatory for V(D)J recombination aside from its role in stabilizing DNA ligase IV. In contrast, Xrcc4M61R mice crossed on Paxx-/-, Nhej1-/-, or Atm-/- backgrounds are severely immunocompromised, owing to aborted V(D)J recombination as in Xlf-Paxx and Xlf-Atm double KO settings. Furthermore, massive apoptosis of post-mitotic neurons causes embryonic lethality of Xrcc4M61R -Nhej1-/- double mutants. These in vivo results reveal new functional interplays between XRCC4 and PAXX, ATM and Xlf in mouse development and provide new insights in the understanding of the clinical manifestations of human XRCC4 deficient condition, in particular its absence of immune deficiency.