TY - JOUR
T1 - An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility
AU - Bosada, Fernanda M.
AU - van Duijvenboden, Karel
AU - Giovou, Alexandra E.
AU - Rivaud, Mathilde R.
AU - Uhm, Jae-Sun
AU - Verkerk, Arie O.
AU - Boukens, Bastiaan J.
AU - Christoffels, Vincent M.
N1 - Funding Information: We thank Berend de Jonge for technical assistance. This work was supported by CardioVasculair Onderzoek Nederland (CVON) project 2014-18 CONCOR-genes Young Talent Program (to F.M.B.), CVON project 2014-18 CONCOR-genes (to V.M.C.), Leducq Foundation 14CVD01 (to V.M.C.), Dutch CardioVascular Alliance OUTREACH (to V.M.C.) and ZonMW TOP 91217061 (to V.M.C.). Publisher Copyright: © 2023, eLife Sciences Publications Ltd. All rights reserved.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85147158757&partnerID=8YFLogxK
U2 - https://doi.org/10.7554/eLife.80317
DO - https://doi.org/10.7554/eLife.80317
M3 - Article
C2 - 36715501
SN - 2050-084X
VL - 12
JO - eLife
JF - eLife
M1 - e80317
ER -