An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility

  1. Fernanda M Bosada
  2. Karel van Duijvenboden
  3. Alexandra E Giovou
  4. Mathilde R Rivaud
  5. Jae-Sun Uhm
  6. Arie O Verkerk
  7. Bastiaan J Boukens
  8. Vincent M Christoffels  Is a corresponding author
  1. Amsterdam University Medical Centers, Netherlands
  2. Yonsei University, Republic of Korea

Abstract

Heart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders, whereas increased expression levels of TBX5 in human heart samples has been associated with atrial fibrillation (AF). We deleted the conserved mouse orthologues of two independent AF-associated genomic regions in the Tbx5 locus, one intronic (RE(int)) and one downstream (RE(down)) of Tbx5. In both lines we observed a modest (30%) increase of Tbx5 in the postnatal atria. To gain insight into the effects of slight dosage increase in vivo, we investigated the atrial transcriptional, epigenetic and electrophysiological properties of both lines. Increased atrial Tbx5 expression was associated with induction of genes involved in development, ion transport and conduction, with increased susceptibility to atrial arrhythmias, and increased action potential duration of atrial cardiomyocytes. We identified an AF-associated variant in the human RE(int) that increases its transcriptional activity. Expression of the AF-associated transcription factor Prrx1 was induced in Tbx5RE(int)KO cardiomyocytes. We found that some of the transcriptional and functional changes in the atria caused by increased Tbx5 expression were normalized when reducing cardiac Prrx1 expression in Tbx5RE(int)KO mice, indicating an interaction between these two AF genes. We conclude that modest increases in expression of dose-dependent transcription factors, caused by common regulatory variants, significantly impact on the cardiac gene regulatory network and disease susceptibility.

Data availability

Adult left atrial RNAseq and ATACseq have been deposited under GEO accession numbers GSE189342 and GSE189498.

The following data sets were generated

Article and author information

Author details

  1. Fernanda M Bosada

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Karel van Duijvenboden

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexandra E Giovou

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Mathilde R Rivaud

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Jae-Sun Uhm

    Department of Cardiology, Yonsei University, Seoul, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  6. Arie O Verkerk

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2140-834X
  7. Bastiaan J Boukens

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Vincent M Christoffels

    Department of Medical Biology, Amsterdam University Medical Centers, Amsterdam, Netherlands
    For correspondence
    v.m.christoffels@amsterdamumc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4131-2636

Funding

CVON project 2014-18 CONCOR-genes (Young Talent Program)

  • Fernanda M Bosada

CVON project 2014-18 CONCOR-genes

  • Vincent M Christoffels

Fondation Leducq (14CVD01)

  • Vincent M Christoffels

Dutch Cardiovascular Alliance (OUTREACH)

  • Vincent M Christoffels

ZonMw (TOP 91217061)

  • Vincent M Christoffels

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

Ethics

Animal experimentation: Housing, husbandry, all animal care and experimental protocols were in accordance with guidelines310 from the Directive 2010/63/EU of the European Parliament and Dutch government. Protocols were311 approved by the Animal Experimental Committee of the Amsterdam University Medical Centers.312 Animal group sizes were determined based on previous experience.

Reviewing Editor

  1. Kalyanam Shivkumar, UCLA Health, United States

Version history

  1. Preprint posted: May 14, 2022 (view preprint)
  2. Received: May 27, 2022
  3. Accepted: January 29, 2023
  4. Accepted Manuscript published: January 30, 2023 (version 1)
  5. Version of Record published: February 14, 2023 (version 2)

Copyright

© 2023, Bosada 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. Fernanda M Bosada
  2. Karel van Duijvenboden
  3. Alexandra E Giovou
  4. Mathilde R Rivaud
  5. Jae-Sun Uhm
  6. Arie O Verkerk
  7. Bastiaan J Boukens
  8. Vincent M Christoffels
(2023)
An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility
eLife 12:e80317.
https://doi.org/10.7554/eLife.80317

Share this article

https://doi.org/10.7554/eLife.80317

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