Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

Liu, Ruya; Lee, Jeongkyung; Kim, Byung S.; Wang, Qiongling; Buxton, Samuel; Balasubramanyam, Nikhil; Kim, Jean J.; Dong, Jianrong; Zhang, Aijun; Li, Shumin; Gupte, Anisha A.; Hamilton, Dale J.; Martin, James F.; Rodney, George G.; Coarfa, Cristian; Wehrens, Xander H.T.; Yechoor, Vijay; Moulik, Mousumi

doi:10.1172/jci.insight.93343

Cited by 51 publications

(65 citation statements)

References 63 publications

(66 reference statements)

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“…Fibroblasts were cultured in alpha MEM (Hyclone) with 10% FBS (Hyclone), 2 mMol/mL L-Glutamine (Hyclone), 50 U/mL penicillin, and 50 mg/mL streptomycin (Hyclone). The HSCC-003iPS (Ctrl 1) cell line was generated using dermal fibroblasts from a 22-year-old healthy male donor (ZenBio, lot # DFM062509), 12 Ctrl 2 cell line from a 61-year-old healthy male donor, and the HSCC-022iPS (Ctrl 4) cell line from a 16-year-old healthy male donor (CRL-2529, ATCC).…”

Section: Rna Isolation and Real-time Qpcrmentioning

confidence: 99%

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Kho

Tian

Wong

et al. 2018

The American Journal of Human Genetics

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Primary hypertension is a major risk factor for ischemic heart disease, stroke, and chronic kidney disease. Insights obtained from the study of rare Mendelian forms of hypertension have been invaluable in elucidating the mechanisms causing primary hypertension and development of antihypertensive therapies. Endothelial cells play a key role in the regulation of blood pressure; however, a Mendelian form of hypertension that is primarily due to endothelial dysfunction has not yet been described. Here, we show that the urea cycle disorder, argininosuccinate lyase deficiency (ASLD), can manifest as a Mendelian form of endothelial-dependent hypertension. Using data from a human clinical study, a mouse model with endothelial-specific deletion of argininosuccinate lyase (Asl), and in vitro studies in human aortic endothelial cells and induced pluripotent stem cell-derived endothelial cells from individuals with ASLD, we show that loss of ASL in endothelial cells leads to endothelial-dependent vascular dysfunction with reduced nitric oxide (NO) production, increased oxidative stress, and impaired angiogenesis. Our findings show that ASLD is a unique model for studying NO-dependent endothelial dysfunction in human hypertension.

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Section: Rna Isolation and Real-time Qpcrmentioning

confidence: 99%

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Kho

Tian

Wong

et al. 2018

The American Journal of Human Genetics

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“…Loss of certain transcription factors such as TEADs (TEF family transcription factors), GATA and FOG (fried of GATA) [22,23,24,25,26,27,28] result in pathophysiologic phenotypes [29] as they are necessary for normal heart development (link to another term found: myoblast differentiation ). TEADs directly interact with pol II and activate and regulate the expression of several genes involved in cardiac muscle contraction (e.g., MYH6 and MYH7, aka myosin heavy chains α and β [22], SERCA2, aka sarcoendoplasmic reticulum Ca2+-ATPase 2a [24], and others [23]). Loss or overexpression of TEAD1 leads to several phenotypes associated with HF such as fibrosis, contractile dysfunction, hypertrophy, and conduction defects [22,23,24].…”

Section: Resultsmentioning

confidence: 99%

“…TEADs directly interact with pol II and activate and regulate the expression of several genes involved in cardiac muscle contraction (e.g., MYH6 and MYH7, aka myosin heavy chains α and β [22], SERCA2, aka sarcoendoplasmic reticulum Ca2+-ATPase 2a [24], and others [23]). Loss or overexpression of TEAD1 leads to several phenotypes associated with HF such as fibrosis, contractile dysfunction, hypertrophy, and conduction defects [22,23,24]. DNA binding protein GATA4 and associated proteins (e.g., MEF2a, aka myocyte-specific enhancer factor 2a, and FOG) are involved in cardiac development and are upregulated in cardiac hypertrophy [25,26,27,28,30,31] (again tying in with the term myoblast differentiation ).…”

Section: Resultsmentioning

confidence: 99%

Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species

et al. 2018

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Genetic model organisms have the potential of removing blind spots from the underlying gene regulatory networks of human diseases. Allowing analyses under experimental conditions they complement the insights gained from observational data. An inevitable requirement for a successful trans-species transfer is an abstract but precise high-level characterization of experimental findings. In this work, we provide a large-scale analysis of seven weak contractility/heart failure genotypes of the model organism zebrafish which all share a weak contractility phenotype. In supervised classification experiments, we screen for discriminative patterns that distinguish between observable phenotypes (homozygous mutant individuals) as well as wild-type (homozygous wild-types) and carriers (heterozygous individuals). As the method of choice we use semantic multi-classifier systems, a knowledge-based approach which constructs hypotheses from a predefined vocabulary of high-level terms (e.g., Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways or Gene Ontology (GO) terms). Evaluating these models leads to a compact description of the underlying processes and guides the screening for new molecular markers of heart failure. Furthermore, we were able to independently corroborate the identified processes in Wistar rats.

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“…Collectively, the early embryonic lethality observed in TEAD1 global KO embryos provides the proof of principle evidence that Cre‐mediated deletion of E3 not only disrupts TEAD1 gene expression but also abolishes the function of TEAD1 in vivo in development. During the preparation of the manuscript, we realized a floxed TEAD1 mouse line was generated using the similar strategy as we described in this study (Liu et al, ). Our current study independently validated this mouse line and extensively characterized the TEAD1 conditional allele in vitro and in vivo .…”

Section: Resultsmentioning

confidence: 99%

Characterization of mice carrying a conditional TEAD1 allele

Wen

Yin

et al. 2017

Genesis

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The Hippo-YAP pathway is essential for controlling organ size and tumorigenesis. Previous studies have demonstrated that the primary outcome of YAP signaling in the nucleus is achieved by interaction with the transcription factor TEAD1. The YAP/TEAD1 complex binds to DNA element and regulates the expression of genes involved in cell growth. However, constitutive knockout of TEAD1 leads to early embryonic lethality in mice. Thus, generation of a floxed TEAD1 mouse becomes crucial for further understanding mid- to late-gestation and post-natal role of TEAD1. Herein, we created and characterized a mouse model that allows for conditional disruption of TEAD1. Embryonic fibroblasts derived from the floxed TEAD1 mice enabled the Cre-mediated deletion of TEAD1 in vitro using virally delivered Cre recombinase. Furthermore, crossing the floxed TEAD1 mouse with a ubiquitously expressing Cre mouse resulted in efficient ablation of the floxed allele in vivo, and the animals recapitulated early embryonic lethality defects. In conclusion, our data demonstrate an important role of TEAD1 in early development in mice, and the floxed TEAD1 mouse model will be a valuable genetic tool to determine the temporal and tissue-specific functions of TEAD1.

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Tead1 is required for maintaining adult cardiomyocyte function, and its loss results in lethal dilated cardiomyopathy

Cited by 51 publications

References 63 publications

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Argininosuccinate Lyase Deficiency Causes an Endothelial-Dependent Form of Hypertension

Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species

Characterization of mice carrying a conditional TEAD1 allele

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