Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer

M. van den Boogaard; L.Y. Wong; F. Tessadori; M.L. Bakker; L.K. Dreizehnter; V. Wakker; C.R. Bezzina; P.A. 't Hoen; J. Bakkers; P. Barnett; V.M. Christoffels

doi:10.1172/JCI62613

Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer

M. van den Boogaard, L.Y. Wong, F. Tessadori, M.L. Bakker, L.K. Dreizehnter, V. Wakker, C.R. Bezzina, P.A. 't Hoen, J. Bakkers, P. Barnett, V.M. Christoffels

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

158 Citaten (Scopus)

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The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system-regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo. Thus, the identification of key regulatory elements for cardiac conduction helps to explain how genetic variants in noncoding regulatory DNA sequences influence the regulation of cardiac conduction and the predisposition for cardiac arrhythmias.

Originele taal-2	Engels
Pagina's (van-tot)	2519-2530
Tijdschrift	Journal of Clinical Investigation
Volume	122
Nummer van het tijdschrift	7
DOI's	https://doi.org/10.1172/JCI62613
Status	Gepubliceerd - 2012

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@article{f437a893adc24ac18e0645c8f3757015,

title = "Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer",

abstract = "The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system-regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo. Thus, the identification of key regulatory elements for cardiac conduction helps to explain how genetic variants in noncoding regulatory DNA sequences influence the regulation of cardiac conduction and the predisposition for cardiac arrhythmias.",

author = "{van den Boogaard}, M. and L.Y. Wong and F. Tessadori and M.L. Bakker and L.K. Dreizehnter and V. Wakker and C.R. Bezzina and {'t Hoen}, P.A. and J. Bakkers and P. Barnett and V.M. Christoffels",

note = "Reporting year: 2012",

year = "2012",

doi = "10.1172/JCI62613",

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T1 - Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer

AU - van den Boogaard, M.

AU - Wong, L.Y.

AU - Tessadori, F.

AU - Bakker, M.L.

AU - Dreizehnter, L.K.

AU - Wakker, V.

AU - Bezzina, C.R.

AU - 't Hoen, P.A.

AU - Bakkers, J.

AU - Barnett, P.

AU - Christoffels, V.M.

N1 - Reporting year: 2012

PY - 2012

Y1 - 2012

N2 - The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system-regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo. Thus, the identification of key regulatory elements for cardiac conduction helps to explain how genetic variants in noncoding regulatory DNA sequences influence the regulation of cardiac conduction and the predisposition for cardiac arrhythmias.

AB - The contraction pattern of the heart relies on the activation and conduction of the electrical impulse. Perturbations of cardiac conduction have been associated with congenital and acquired arrhythmias as well as cardiac arrest. The pattern of conduction depends on the regulation of heterogeneous gene expression by key transcription factors and transcriptional enhancers. Here, we assessed the genome-wide occupation of conduction system-regulating transcription factors TBX3, NKX2-5, and GATA4 and of enhancer-associated coactivator p300 in the mouse heart, uncovering cardiac enhancers throughout the genome. Many of the enhancers colocalized with ion channel genes repressed by TBX3, including the clustered sodium channel genes Scn5a, essential for cardiac function, and Scn10a. We identified 2 enhancers in the Scn5a/Scn10a locus, which were regulated by TBX3 and its family member and activator, TBX5, and are functionally conserved in humans. We also provided evidence that a SNP in the SCN10A enhancer associated with alterations in cardiac conduction patterns in humans disrupts TBX3/TBX5 binding and reduces the cardiac activity of the enhancer in vivo. Thus, the identification of key regulatory elements for cardiac conduction helps to explain how genetic variants in noncoding regulatory DNA sequences influence the regulation of cardiac conduction and the predisposition for cardiac arrhythmias.

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DO - 10.1172/JCI62613

M3 - Article

SN - 0021-9738

VL - 122

SP - 2519

EP - 2530

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 7

ER -

Genetic variation in T-box binding element functionally affects SCN5A/SCN10A enhancer

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