MEF2C regulates outflow tract alignment and transcriptional control of <i>Tdgf1</i>

Barnes, Ralston M.; Harris, I.; Jaehnig, Eric J.; Sauls, Kimberly; Sinha, Tanvi; Rojas, Anabel; Schachterle, William; McCulley, David J.; Norris, Russell A.; Black, Brian L.

doi:10.1242/dev.126383

Cited by 41 publications

(49 citation statements)

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“…This aberrant DNA methylation was associated with decreased mRNA expression of these two transcription factors, suggesting that DNA methylation plays a key role in transcriptional regulation and pathophysiology of TOF. Similarly, the histone methyltransferase G9a is well‐known to regulate the expression of MEF2C , a transcription factor associated with outflow tract anomalies . While we are learning the importance of transcription factors in the development of CHD, it will be vital to understand the epigenetic regulation of transcription factors.…”

Section: Impact Of Epigenetics In Congenital and Acquired Pediatric Hmentioning

confidence: 99%

“…Similarly, the histone methyltransferase G9a is well-known to regulate the expression of MEF2C, a transcription factor associated with outflow tract anomalies. [23][24][25] While we are learning the importance of transcription factors in the development of CHD, it will be vital to understand the epigenetic regulation of transcription factors.…”

Section: M P a Ct Of E P I Gen E Ti Cs I N Con Ge N It Al A N D Amentioning

confidence: 99%

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Epigenetics for the pediatric cardiologist

Spearman

2017

Congenital Heart Disease

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A genetic basis of congenital heart disease (CHD) has been known for decades. In addition to the sequence of the genome, the contribution of epigenetics to pediatric cardiology is increasingly recognized. Multiple epigenetic mechanisms, including DNA methylation, histone modification, and RNA-based regulation, are known mediators of cardiovascular disease, including both development and progression of CHD and its sequelae. Basic understanding of the concepts of epigenetics will be essential to all pediatric cardiologists in order to understand mechanisms of pathophysiology, pharmacotherapeutic concepts, and to understand the role of epigenetics in precision medicine.

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Section: Impact Of Epigenetics In Congenital and Acquired Pediatric Hmentioning

confidence: 99%

Section: M P a Ct Of E P I Gen E Ti Cs I N Con Ge N It Al A N D Amentioning

confidence: 99%

Epigenetics for the pediatric cardiologist

Spearman

2017

Congenital Heart Disease

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“…This approach was used to study the role of Mef2c, a key cardiogenic TF (Lin et al, 1997), in outflow tract (OFT) development (Barnes et al, 2016). The murine conditional loss-of-function model Myocyte Enhancer Factor 2C-conditional gene knockout (Mef2c-CKO) recapitulated OFT alignment defects seen in a human CHD patient harboring a mutation in Mef2c (Kodo et al, 2012).…”

Section: Transcriptomic Analyses Of Cardiac Developmentmentioning

confidence: 99%

Emerging Field of Cardiomics: High-Throughput Investigations into Transcriptional Regulation of Cardiovascular Development and Disease

Slagle

Conlon

2016

Trends in Genetics

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Congenital heart defects remain a leading cause of infant mortality in the western world, despite decades of research focusing on cardiovascular development and disease,. With the recent emergence of several high-throughput technologies including RNA sequencing, chromatin immunoprecipitation-coupled sequencing, mass spectrometry-based proteomics analyses, and the numerous variations of these strategies, investigations into cardiac development have been transformed from candidate-based studies into whole-genome, -transcriptome, and -proteome undertakings. In this review, we discuss several reports that have emerged from our lab and others over the last five years that emphasize the versatility of large dataset-based investigations of cardiogenic transcription factors, from phenotypic validations and new gene implications to the identification of novel roles of well-studied transcriptional regulators. Broadening the understanding of cardiac development and diseaseA growing body of work has indicated an association between mutations in several transcription factors (TFs) and congenital heart disease (CHD) (Bruneau, 2013; Prendiville et al., 2014), highlighting the need to elucidate the transcriptional regulation of various aspects of cardiovascular development. High-throughput technologies have dramatically broadened the capacity in which to study regulators of gene networks (see Figure 1 for an overview of the main high-throughput technologies discussed here). High-throughput sequencing of a cell's transcriptional profile (RNA-seq) allows for comparison of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.

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“…The anterior SHF is essential for OFT and great artery development [5-9]. The failure of the anterior SHF-derived myocardial and endocardial contributions to the arterial pole of the heart causes a shortened OFT and arterial pole misalignment, resulting in inappropriate connections of the great arteries to the ventricular mass [10-12]. Deletion of genes responsible for SHF morphogenesis, such as Isl1 , Mef2c , and Jagged1 , leads to abnormal OFT formation including DORV [5, 6, 8, 12-19].…”

Section: Introductionmentioning

confidence: 99%

“…However, the mechanistic requirement for Gata4 in OFT development is less clear. For example, from the multiple Gata4 transcriptional targets that have been identified in the context of heart development, including Nppa, α-MHC, α-CA, B-type natriuretic peptide ( BNP ) , Ccnd2 , and Cyclin D2 , and Mef2c [20, 23, 24, 26, 43, 44], only Mef2c has a functional role in OFT development [12].…”

Section: Introductionmentioning

confidence: 99%

Gata4 drives Hh-signaling for second heart field migration and outflow tract development

Liu

Cheng

Xiang

et al. 2018

Preprint

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32Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), cause 33 outflow tract (OFT) defects in both human and mouse. We investigated the molecular 34 mechanism underlying this requirement. Gata4 happloinsufficiency in mice caused OFT 35 defects including double outlet right ventricle (DORV) and conal ventricular septum 36 defects (VSDs). We found that Gata4 is required within Hedgehog (Hh)-receiving second 37 heart field (SHF) progenitors for normal OFT alignment. Increased Pten-mediated cell-38 cycle transition, rescued atrial septal defects but not OFT defects in Gata4 heterozygotes. 39 SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion in Gata4 40 heterozygote embryos. We find that Hh signaling and Gata4 genetically interact for OFT 41 development. Gata4 and Smo double heterozygotes displayed more severe OFT 42 abnormalities including persistent truncus arteriosus (PTA) whereas restoration of 43 Hedgehog signaling rescued OFT defects in Gata4-mutant mice. In addition, enhanced 44 expression of the Gata6 was observed in the SHF of the Gata4 heterozygotes. These 45 results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling 46 for OFT development. This study indicates that Gata4 potentiation of Hh signaling is a 47 general feature of Gata4-mediated cardiac morphogenesis and provides a model for the 48 molecular basis of CHD caused by dominant transcription factor mutations.49 3 50Gata4 is an important protein that controls the development of the heart. Human who 52 possess a single copy of Gata4 mutation display congenital heart defects (CHD), 53 including the double outlet right ventricle (DORV). DORV is an alignment problem in 54 which both the Aorta and Pulmonary Artery originate from the right ventricle, instead of 55 originating from the left and the right ventricles, respectively. To study how Gata4 56 mutation causes DORV, we used a Gata4 mutant mouse model, which displays DORV. 57We showed that Gata4 is required in the cardiac precursor cells for the normal alignment 58 of the great arteries. Although Gata4 mutation inhibits the rapid increase in number of the 59 cardiac precursor cells, rescuing this defects does not recover the normal alignment of 60 the great arteries. In addition, there is a movement problem of the cardiac precursor cells 61 when migrating toward the great arteries during development. We further showed that a 62 specific molecular signaling, Hh-signaling, is responsible to the Gata4 action in the 63 cardiac precursor cells. Importantly, over-activating the Hh-signaling rescues the DORV 64 in the Gata4 mutant embryos. This study provides an explanation for the ontogeny of 65 CHD. 66 4 67 Introduction 68 Congenital Heart Defects (CHDs) CHDs occurr in approximately 1% of live births [1] 69 and are the most common serious birth defects in humans [2, 3]. Approximately one third 70 of the CHDs involve malformations of the outflow tract (OFT), which leads to significant 71 morbidity and mortality o...

show abstract

MEF2C regulates outflow tract alignment and transcriptional control of Tdgf1

Cited by 41 publications

References 48 publications

Epigenetics for the pediatric cardiologist

Epigenetics for the pediatric cardiologist

Emerging Field of Cardiomics: High-Throughput Investigations into Transcriptional Regulation of Cardiovascular Development and Disease

Gata4 drives Hh-signaling for second heart field migration and outflow tract development

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