T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system

Genome-wide association studies have identified noncoding variants near TBX3 that are associated with PR interval and QRS duration, suggesting that subtle changes in TBX3 expression affect atrioventricular conduction system function. To explore whether and to what extent the atrioventricular conduct...

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Auteurs principaux: Mohan, RA, Bosada, FM, van Weerd, JH, van Duijvenboden, K, Wang, J, Mommersteeg, MTM, Hooijkaas, IB, Wakker, V, de Gier-de Vries, C, Coronel, R, Boink, GJJ, Bakkers, J, Barnett, P, Boukens, BJ, Christoffels, VM
Format: Journal article
Langue:English
Publié: National Academy of Sciences 2020
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author Mohan, RA
Bosada, FM
van Weerd, JH
van Duijvenboden, K
Wang, J
Mommersteeg, MTM
Hooijkaas, IB
Wakker, V
de Gier-de Vries, C
Coronel, R
Boink, GJJ
Bakkers, J
Barnett, P
Boukens, BJ
Christoffels, VM
author_facet Mohan, RA
Bosada, FM
van Weerd, JH
van Duijvenboden, K
Wang, J
Mommersteeg, MTM
Hooijkaas, IB
Wakker, V
de Gier-de Vries, C
Coronel, R
Boink, GJJ
Bakkers, J
Barnett, P
Boukens, BJ
Christoffels, VM
author_sort Mohan, RA
collection OXFORD
description Genome-wide association studies have identified noncoding variants near TBX3 that are associated with PR interval and QRS duration, suggesting that subtle changes in TBX3 expression affect atrioventricular conduction system function. To explore whether and to what extent the atrioventricular conduction system is affected by Tbx3 dose reduction, we first characterized electrophysiological properties and morphology of heterozygous Tbx3 mutant (Tbx3 +/-) mouse hearts. We found PR interval shortening and prolonged QRS duration, as well as atrioventricular bundle hypoplasia after birth in heterozygous mice. The atrioventricular node size was unaffected. Transcriptomic analysis of atrioventricular nodes isolated by laser capture microdissection revealed hundreds of deregulated genes in Tbx3 +/- mutants. Notably, Tbx3 +/- atrioventricular nodes showed increased expression of working myocardial gene programs (mitochondrial and metabolic processes, muscle contractility) and reduced expression of pacemaker gene programs (neuronal, Wnt signaling, calcium/ion channel activity). By integrating chromatin accessibility profiles (ATAC sequencing) of atrioventricular tissue and other epigenetic data, we identified Tbx3-dependent atrioventricular regulatory DNA elements (REs) on a genome-wide scale. We used transgenic reporter assays to determine the functionality of candidate REs near Ryr2, an up-regulated chamber-enriched gene, and in Cacna1g, a down-regulated conduction system-specific gene. Using genome editing to delete candidate REs, we showed that a strong intronic bipartite RE selectively governs Cacna1g expression in the conduction system in vivo. Our data provide insights into the multifactorial Tbx3-dependent transcriptional network that regulates the structure and function of the cardiac conduction system, which may underlie the differences in PR duration and QRS interval between individuals carrying variants in the TBX3 locus.
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spelling oxford-uuid:e03d99b7-0bb7-43f4-af1f-df126e7590942022-03-27T09:45:46ZT-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction systemJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e03d99b7-0bb7-43f4-af1f-df126e759094EnglishSymplectic ElementsNational Academy of Sciences2020Mohan, RABosada, FMvan Weerd, JHvan Duijvenboden, KWang, JMommersteeg, MTMHooijkaas, IBWakker, Vde Gier-de Vries, CCoronel, RBoink, GJJBakkers, JBarnett, PBoukens, BJChristoffels, VMGenome-wide association studies have identified noncoding variants near TBX3 that are associated with PR interval and QRS duration, suggesting that subtle changes in TBX3 expression affect atrioventricular conduction system function. To explore whether and to what extent the atrioventricular conduction system is affected by Tbx3 dose reduction, we first characterized electrophysiological properties and morphology of heterozygous Tbx3 mutant (Tbx3 +/-) mouse hearts. We found PR interval shortening and prolonged QRS duration, as well as atrioventricular bundle hypoplasia after birth in heterozygous mice. The atrioventricular node size was unaffected. Transcriptomic analysis of atrioventricular nodes isolated by laser capture microdissection revealed hundreds of deregulated genes in Tbx3 +/- mutants. Notably, Tbx3 +/- atrioventricular nodes showed increased expression of working myocardial gene programs (mitochondrial and metabolic processes, muscle contractility) and reduced expression of pacemaker gene programs (neuronal, Wnt signaling, calcium/ion channel activity). By integrating chromatin accessibility profiles (ATAC sequencing) of atrioventricular tissue and other epigenetic data, we identified Tbx3-dependent atrioventricular regulatory DNA elements (REs) on a genome-wide scale. We used transgenic reporter assays to determine the functionality of candidate REs near Ryr2, an up-regulated chamber-enriched gene, and in Cacna1g, a down-regulated conduction system-specific gene. Using genome editing to delete candidate REs, we showed that a strong intronic bipartite RE selectively governs Cacna1g expression in the conduction system in vivo. Our data provide insights into the multifactorial Tbx3-dependent transcriptional network that regulates the structure and function of the cardiac conduction system, which may underlie the differences in PR duration and QRS interval between individuals carrying variants in the TBX3 locus.
spellingShingle Mohan, RA
Bosada, FM
van Weerd, JH
van Duijvenboden, K
Wang, J
Mommersteeg, MTM
Hooijkaas, IB
Wakker, V
de Gier-de Vries, C
Coronel, R
Boink, GJJ
Bakkers, J
Barnett, P
Boukens, BJ
Christoffels, VM
T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
title T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
title_full T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
title_fullStr T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
title_full_unstemmed T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
title_short T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
title_sort t box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
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