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

Proceedings of the National Academy of Sciences of the United States of America
Rajiv A MohanVincent M Christoffels

Abstract

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 atrioventricul...Continue Reading

References

Jan 1, 1982·Developmental Biology·S Virágh, C E Challice
Nov 1, 1996·The American Journal of Physiology·M H SoonpaaL J Field
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·M l HeY Rao
May 26, 2004·Cardiovascular Research·Willem M H HoogaarsVincent M Christoffels
Jun 15, 2004·Cardiovascular Research·Lucile MiquerolDaniel Gros
Oct 23, 2004·The Journal of Physiology·Céline MarionneauSophie Demolombe
Jul 28, 2006·Developmental Biology·Alessandro D MoriBenoit G Bruneau
May 3, 2007·Genes & Development·Willem M H HoogaarsVincent M Christoffels
May 10, 2008·Circulation Research·Martijn L BakkerVincent M Christoffels
Dec 19, 2008·Development·Catherine A RisebroPaul R Riley
Aug 8, 2009·Circulation Research·Reena SinghAndreas Kispert
Jan 12, 2010·Nature Genetics·Arne PfeuferSusan R Heckbert
Jan 30, 2010·Cardiovascular Research·Larissa FabritzPaulus Kirchhof
Jan 25, 2011·Journal of Molecular and Cellular Cardiology·I D GreenerH Dobrzynski
Jan 27, 2011·The Journal of Clinical Investigation·Wim T J AanhaanenVincent M Christoffels
Jan 27, 2011·The Journal of Clinical Investigation·Stacey RentschlerJonathan A Epstein
May 14, 2011·Birth Defects Research. Part A, Clinical and Molecular Teratology·Manon C VerhoevenJeroen Bakkers
Dec 2, 2011·Cellular and Molecular Life Sciences : CMLS·Reena SinghVincent M Christoffels
Dec 29, 2011·Proceedings of the National Academy of Sciences of the United States of America·Deborah U FrankAnne M Moon
May 26, 2012·Circulation Research·Nikhil V Munshi
Jun 19, 2012·The Journal of Clinical Investigation·Malou van den BoogaardVincent M Christoffels
Jun 26, 2012·The Journal of Clinical Investigation·David E ArnoldsIvan P Moskowitz
Mar 26, 2013·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Lucile MiquerolRobert G Kelly
Jun 8, 2013·Circulation Research·Xingqun LiangSylvia M Evans
Nov 28, 2013·Genesis : the Journal of Genetics and Development·Meng WuYong Zhao
Apr 29, 2014·Nature Communications·Sonia StefanovicVincent M Christoffels
May 23, 2014·Circulation. Cardiovascular Genetics·Niek VerweijPim van der Harst
Jun 26, 2014·Circulation Research·Jan Hendrik van WeerdVincent M Christoffels
Jun 25, 2015·Circulation Research·Sebastian PreisslRalf Gilsbach
Nov 5, 2015·Nucleic Acids Research·Karel van DuijvenbodenVincent M Christoffels
Nov 7, 2015·Cell·Mark H SoonpaaLoren J Field
Sep 24, 2016·Journal of the American College of Cardiology·Pim van der HarstPaul I W de Bakker
Nov 9, 2016·Nature Reviews. Molecular Cell Biology·Peter Hugo Lodewijk Krijger, Wouter de Laat

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Citations

Jun 8, 2021·Circulation Research·Fernanda M BosadaBastiaan J Boukens
Jun 3, 2021·Journal of Cardiovascular Development and Disease·Mohamad AlzeinDiego Franco
Jul 3, 2021·Journal of Cardiovascular Development and Disease·Mathilde R RivaudBastiaan J Boukens
Jul 2, 2021·Current Cardiology Reports·Sruthi MantriWilliam R Goodyer
Aug 13, 2021·Nature Reviews. Cardiology·Chukwuemeka G Anene-NzeluRoger S Y Foo

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