Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development
Mutations in the transcription factor TBX20 are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by E9.5. As Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endode...
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| Veröffentlicht in: | Circulation research Jg. 123; H. 4; S. 428 |
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03.08.2018
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| Abstract | Mutations in the transcription factor TBX20 are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by E9.5. As Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type specific requirement for Tbx20 in early myocardial development remains to be explored.
Here, we investigated roles of
in mid-gestation cardiomyocytes for heart development.
Ablation of
from developing cardiomyocytes using a doxycycline inducible cTnTCre transgene led to embryonic lethality. The circumference of developing ventricular and atrial chambers, and in particular that of prospective left atrium was significantly reduced in
Cell cycle analysis demonstrated reduced proliferation of
mutant cardiomyocytes, and their arrest at the G1-S phase transition. Genome-wide transcriptome analysis of mutant cardiomyocytes revealed differential expression of multiple genes critical for cell cycle regulation. Moreover, atrial and ventricular gene programs appeared to be aberrantly regulated. Putative direct TBX20 targets were identified using TBX20 ChIP-Seq from embryonic heart and included key cell cycle genes, and atrial and ventricular specific genes. Notably, TBX20 bound a conserved enhancer for a gene key to atrial development and identity,
This enhancer interacted with the
promoter in human cardiomyocytes and conferred atrial specific gene expression in a transgenic mouse in a TBX20 dependent manner.
Myocardial TBX20 directly regulates a subset of genes required for fetal cardiomyocyte proliferation, including those required for the G1-S transition. TBX20 also directly downregulates progenitor-specific genes and, in addition to regulating genes that specify chamber versus non-chamber myocardium, directly activates genes required for establishment or maintenance of atrial and ventricular identity. TBX20 plays a previously unappreciated key role in atrial development through direct regulation of an evolutionarily conserved
enhancer. |
|---|---|
| AbstractList | Mutations in the transcription factor TBX20 (T-box 20) are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by embryonic day 9.5. Because Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type-specific requirement for TBX20 in early myocardial development remains to be explored.RATIONALEMutations in the transcription factor TBX20 (T-box 20) are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by embryonic day 9.5. Because Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type-specific requirement for TBX20 in early myocardial development remains to be explored.Here, we investigated roles of TBX20 in midgestation cardiomyocytes for heart development.OBJECTIVEHere, we investigated roles of TBX20 in midgestation cardiomyocytes for heart development.Ablation of Tbx20 from developing cardiomyocytes using a doxycycline inducible cTnTCre transgene led to embryonic lethality. The circumference of developing ventricular and atrial chambers, and in particular that of prospective left atrium, was significantly reduced in Tbx20 conditional knockout mutants. Cell cycle analysis demonstrated reduced proliferation of Tbx20 mutant cardiomyocytes and their arrest at the G1-S phase transition. Genome-wide transcriptome analysis of mutant cardiomyocytes revealed differential expression of multiple genes critical for cell cycle regulation. Moreover, atrial and ventricular gene programs seemed to be aberrantly regulated. Putative direct TBX20 targets were identified using TBX20 ChIP-Seq (chromatin immunoprecipitation with high throughput sequencing) from embryonic heart and included key cell cycle genes and atrial and ventricular specific genes. Notably, TBX20 bound a conserved enhancer for a gene key to atrial development and identity, COUP-TFII/Nr2f2 (chicken ovalbumin upstream promoter transcription factor 2/nuclear receptor subfamily 2, group F, member 2). This enhancer interacted with the NR2F2 promoter in human cardiomyocytes and conferred atrial specific gene expression in a transgenic mouse in a TBX20-dependent manner.METHODS AND RESULTSAblation of Tbx20 from developing cardiomyocytes using a doxycycline inducible cTnTCre transgene led to embryonic lethality. The circumference of developing ventricular and atrial chambers, and in particular that of prospective left atrium, was significantly reduced in Tbx20 conditional knockout mutants. Cell cycle analysis demonstrated reduced proliferation of Tbx20 mutant cardiomyocytes and their arrest at the G1-S phase transition. Genome-wide transcriptome analysis of mutant cardiomyocytes revealed differential expression of multiple genes critical for cell cycle regulation. Moreover, atrial and ventricular gene programs seemed to be aberrantly regulated. Putative direct TBX20 targets were identified using TBX20 ChIP-Seq (chromatin immunoprecipitation with high throughput sequencing) from embryonic heart and included key cell cycle genes and atrial and ventricular specific genes. Notably, TBX20 bound a conserved enhancer for a gene key to atrial development and identity, COUP-TFII/Nr2f2 (chicken ovalbumin upstream promoter transcription factor 2/nuclear receptor subfamily 2, group F, member 2). This enhancer interacted with the NR2F2 promoter in human cardiomyocytes and conferred atrial specific gene expression in a transgenic mouse in a TBX20-dependent manner.Myocardial TBX20 directly regulates a subset of genes required for fetal cardiomyocyte proliferation, including those required for the G1-S transition. TBX20 also directly downregulates progenitor-specific genes and, in addition to regulating genes that specify chamber versus nonchamber myocardium, directly activates genes required for establishment or maintenance of atrial and ventricular identity. TBX20 plays a previously unappreciated key role in atrial development through direct regulation of an evolutionarily conserved COUPT-FII enhancer.CONCLUSIONSMyocardial TBX20 directly regulates a subset of genes required for fetal cardiomyocyte proliferation, including those required for the G1-S transition. TBX20 also directly downregulates progenitor-specific genes and, in addition to regulating genes that specify chamber versus nonchamber myocardium, directly activates genes required for establishment or maintenance of atrial and ventricular identity. TBX20 plays a previously unappreciated key role in atrial development through direct regulation of an evolutionarily conserved COUPT-FII enhancer. Mutations in the transcription factor TBX20 are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by E9.5. As Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type specific requirement for Tbx20 in early myocardial development remains to be explored. Here, we investigated roles of in mid-gestation cardiomyocytes for heart development. Ablation of from developing cardiomyocytes using a doxycycline inducible cTnTCre transgene led to embryonic lethality. The circumference of developing ventricular and atrial chambers, and in particular that of prospective left atrium was significantly reduced in Cell cycle analysis demonstrated reduced proliferation of mutant cardiomyocytes, and their arrest at the G1-S phase transition. Genome-wide transcriptome analysis of mutant cardiomyocytes revealed differential expression of multiple genes critical for cell cycle regulation. Moreover, atrial and ventricular gene programs appeared to be aberrantly regulated. Putative direct TBX20 targets were identified using TBX20 ChIP-Seq from embryonic heart and included key cell cycle genes, and atrial and ventricular specific genes. Notably, TBX20 bound a conserved enhancer for a gene key to atrial development and identity, This enhancer interacted with the promoter in human cardiomyocytes and conferred atrial specific gene expression in a transgenic mouse in a TBX20 dependent manner. Myocardial TBX20 directly regulates a subset of genes required for fetal cardiomyocyte proliferation, including those required for the G1-S transition. TBX20 also directly downregulates progenitor-specific genes and, in addition to regulating genes that specify chamber versus non-chamber myocardium, directly activates genes required for establishment or maintenance of atrial and ventricular identity. TBX20 plays a previously unappreciated key role in atrial development through direct regulation of an evolutionarily conserved enhancer. |
| Author | Montefiori, Lindsey E Zhou, Bin Sobreira, Debora R Bogomolovas, Julius Zhang, Lunfeng Nobrega, Marcelo Evans, Sylvia M Joslin, Amelia C Boogerd, Cornelis J Zhu, Xiaoming Aneas, Ivy Sakabe, Noboru J Chen, Ju |
| Author_xml | – sequence: 1 givenname: Cornelis J surname: Boogerd fullname: Boogerd, Cornelis J organization: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego – sequence: 2 givenname: Xiaoming surname: Zhu fullname: Zhu, Xiaoming organization: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego – sequence: 3 givenname: Ivy surname: Aneas fullname: Aneas, Ivy organization: Human Genetics, University of Chicago – sequence: 4 givenname: Noboru J surname: Sakabe fullname: Sakabe, Noboru J organization: Human Genetics, University of Chicago – sequence: 5 givenname: Lunfeng surname: Zhang fullname: Zhang, Lunfeng organization: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego – sequence: 6 givenname: Debora R surname: Sobreira fullname: Sobreira, Debora R organization: Human Genetics, University of Chicago – sequence: 7 givenname: Lindsey E surname: Montefiori fullname: Montefiori, Lindsey E organization: Human Genetics, University of Chicago – sequence: 8 givenname: Julius surname: Bogomolovas fullname: Bogomolovas, Julius organization: Medicine, University of California San Diego – sequence: 9 givenname: Amelia C surname: Joslin fullname: Joslin, Amelia C organization: Human Genetics, University of Chicago – sequence: 10 givenname: Bin surname: Zhou fullname: Zhou, Bin organization: Genetics, Albert Einstein College of Medicine – sequence: 11 givenname: Ju surname: Chen fullname: Chen, Ju organization: Medicine, University of California San Diego – sequence: 12 givenname: Marcelo surname: Nobrega fullname: Nobrega, Marcelo organization: Human Genetics, University of Chicago – sequence: 13 givenname: Sylvia M surname: Evans fullname: Evans, Sylvia M email: syevans@ucsd.edu organization: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego syevans@ucsd.edu |
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| Snippet | Mutations in the transcription factor TBX20 are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and... Mutations in the transcription factor TBX20 (T-box 20) are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart... |
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| Title | Tbx20 Is Required in Mid-Gestation Cardiomyocytes and Plays a Central Role in Atrial Development |
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