TAF1 bromodomain inhibition as a candidate epigenetic driver of congenital heart disease.

Heart formation requires transcriptional regulators that underlie congenital anomalies and the fetal gene program activated during heart failure. Attributing the effects of congenital heart disease (CHD) missense variants to disruption of specific protein domains allows for a mechanistic understanding of CHDs and improved diagnostics. A combined chemical and genetic approach was employed to identify novel CHD drivers, consisting of chemical screening during pluripotent stem cell (PSC) differentiation, gene expression analyses of native tissues and primary cell culture models, and the in vitro study of damaging missense variants from CHD patients.

GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line.

Background: Pharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable.

Cholecystokinin peptide signaling is regulated by a TBX5-MEF2 axis in the heart.

The procholecystokinin (proCCK) gene encodes a secreted peptide known to regulate the digestive, endocrine, and nervous systems. Though recently proposed as a biomarker for heart dysfunction, its physiological role in both the embryonic and adult heart is poorly understood, and there are no reports of tissue-specific regulators of cholecystokinin signaling in the heart or other tissues. In the present study, mRNA of proCCK was observed in cardiac tissues during mouse embryonic development, establishing proCCK as an early marker of differentiated cardiomyocytes which is later restricted to anatomical subdomains of the neonatal heart.

A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior-posterior patterning of the heart.

Reliable in vitro models to assess developmental toxicity of drugs and chemicals would lead to improvement in fetal safety and a reduced cost of drug development. The validated embryonic stem cell test (EST) uses cardiac differentiation of mouse embryonic stem cells (mESCs) to predict in vivo developmental toxicity, but does not take into account the stage-specific patterning of progenitor populations into anterior (ventricular) and posterior (atrial) compartments. In this study, we generated a novel dual reporter mESC line with fluorescent reporters under the control of anterior and posterior cardiac promoters.

Stem cells are the most sensitive screening tool to identify toxicity of GATA4-targeted novel small-molecule compounds.

Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure-toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4.