The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia

Carolin Rommel; Stephan Rösner; Achim Lother; Margareta Barg; Martin Schwaderer; Ralf Gilsbach; Timo Bömicke; Tilman Schnick; Sandra Mayer; Sophia Doll; Michael Hesse; Oliver Kretz; Brigitte Stiller; Franz-Josef Neumann; Matthias Mann; Markus Krane; Bernd K Fleischmann; Ursula Ravens; Lutz Hein

doi:10.1161/circresaha.118.313036

The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia

Carolin Rommel, Stephan Rösner, Achim Lother, Margareta Barg, Martin Schwaderer, Ralf Gilsbach, Timo Bömicke, Tilman Schnick, Sandra Mayer, Sophia Doll, Michael Hesse, Oliver Kretz, Brigitte Stiller, Franz-Josef Neumann, Matthias Mann, Markus Krane, Bernd K Fleischmann, Ursula Ravens, Lutz Hein

11 Citationer (Scopus)

Abstract

Rationale: Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. Objective: Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. Methods and Results: The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocytespecific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cisregulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposaseaccessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca2+ handling or gap junction formation (Ryr2, Jph2, Gja5), potassium channels (Kcnh2, Kcnk3), and genes implicated in atrial fibrillation (Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. Conclusions: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.

Originalsprog	Engelsk
Tidsskrift	Circulation Research
Vol/bind	123
Udgave nummer	5
Sider (fra-til)	550-563
Antal sider	14
ISSN	0009-7322
DOI	https://doi.org/10.1161/circresaha.118.313036
Status	Udgivet - 2018
Udgivet eksternt	Ja

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10.1161/circresaha.118.313036

CIRCRESAHA.118.313036Forlagets udgivne version, 9,88 MB

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Rommel, C., Rösner, S., Lother, A., Barg, M., Schwaderer, M., Gilsbach, R., Bömicke, T., Schnick, T., Mayer, S., Doll, S., Hesse, M., Kretz, O., Stiller, B., Neumann, F-J., Mann, M., Krane, M., Fleischmann, B. K., Ravens, U., & Hein, L. (2018). The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia. Circulation Research, 123(5), 550-563. https://doi.org/10.1161/circresaha.118.313036

Rommel, C, Rösner, S, Lother, A, Barg, M, Schwaderer, M, Gilsbach, R, Bömicke, T, Schnick, T, Mayer, S, Doll, S, Hesse, M, Kretz, O, Stiller, B, Neumann, F-J, Mann, M, Krane, M, Fleischmann, BK, Ravens, U & Hein, L 2018, 'The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia', Circulation Research, bind 123, nr. 5, s. 550-563. https://doi.org/10.1161/circresaha.118.313036

@article{64f11a4cb8d148cab29c85aaa39c7f37,

title = "The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia",

abstract = "Rationale: Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. Objective: Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. Methods and Results: The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocytespecific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cisregulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposaseaccessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca2+ handling or gap junction formation (Ryr2, Jph2, Gja5), potassium channels (Kcnh2, Kcnk3), and genes implicated in atrial fibrillation (Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. Conclusions: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.",

author = "Carolin Rommel and Stephan R{\"o}sner and Achim Lother and Margareta Barg and Martin Schwaderer and Ralf Gilsbach and Timo B{\"o}micke and Tilman Schnick and Sandra Mayer and Sophia Doll and Michael Hesse and Oliver Kretz and Brigitte Stiller and Franz-Josef Neumann and Matthias Mann and Markus Krane and Fleischmann, {Bernd K} and Ursula Ravens and Lutz Hein",

year = "2018",

doi = "10.1161/circresaha.118.313036",

language = "English",

volume = "123",

pages = "550--563",

journal = "Circulation",

issn = "0009-7322",

publisher = "AHA/ASA",

number = "5",

}

TY - JOUR

T1 - The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia

AU - Rommel, Carolin

AU - Rösner, Stephan

AU - Lother, Achim

AU - Barg, Margareta

AU - Schwaderer, Martin

AU - Gilsbach, Ralf

AU - Bömicke, Timo

AU - Schnick, Tilman

AU - Mayer, Sandra

AU - Doll, Sophia

AU - Hesse, Michael

AU - Kretz, Oliver

AU - Stiller, Brigitte

AU - Neumann, Franz-Josef

AU - Mann, Matthias

AU - Krane, Markus

AU - Fleischmann, Bernd K

AU - Ravens, Ursula

AU - Hein, Lutz

PY - 2018

Y1 - 2018

N2 - Rationale: Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. Objective: Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. Methods and Results: The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocytespecific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cisregulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposaseaccessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca2+ handling or gap junction formation (Ryr2, Jph2, Gja5), potassium channels (Kcnh2, Kcnk3), and genes implicated in atrial fibrillation (Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. Conclusions: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.

AB - Rationale: Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria. Objective: Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes. Methods and Results: The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocytespecific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cisregulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposaseaccessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca2+ handling or gap junction formation (Ryr2, Jph2, Gja5), potassium channels (Kcnh2, Kcnk3), and genes implicated in atrial fibrillation (Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation. Conclusions: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.

U2 - 10.1161/circresaha.118.313036

DO - 10.1161/circresaha.118.313036

M3 - Journal article

C2 - 29930145

SN - 0009-7322

VL - 123

SP - 550

EP - 563

JO - Circulation

JF - Circulation

IS - 5

ER -

The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia

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