Circulation Research Thematic Synopsis Cardiovascular Genetics The Editors

Rationale Wt1-Cre-based tools are important reagents for studying epicardial cell fate and gene function. To better describe the properties of Wt1-Cre-based tools to enhance their use in Cre-loxP-based experiments. In contrast to recently reported results, we show that constitutive Wt1GFPCre in combination with certain Cre-activated reporters can be used to trace (pro) epicardial cell fate. Wt1CreERT2 can be efficiently induced by tamoxifen administration. We show substantial labeling of coronary endothelial cells when induction is performed at late but not early stages of heart Abstract Heart function requires sophisticated regulatory networks to orchestrate organ development, physiological responses, and environmental adaptation. Until recently, it was thought that these regulatory networks are composed solely of pro-tein-mediated transcriptional control and signaling systems; consequently, it was thought that cardiac disease involves perturbation of these systems. However, it is becoming evi-dent that RNA, long considered to function primarily as the , Abstract The advent of modern mouse genetics has benefited many fields of diseased-based research over the past 20 years, none perhaps more profoundly than cardiac biology. Indeed, the heart is now arguably one of the easiest tissues to genetically manipulate, given the availability of an ever-growing tool chest of molecular reagents/promoters and “facilitator” mouse lines. It is now possible to modify the expression of essentially any gene or partial gene product in the mouse heart at any time, either gain or loss of function. This review is designed as a handbook for the nonmouse geneticist and/ or junior investigator to permit the successful manipulation of any gene or RNA product in the heart, while avoiding arti-facts. In the present review, guidelines, pitfalls, and limitations are presented so that rigorous and appropriate examination of cardiac genotype-phenotype relationships can be performed. Abstract In this Emerging Science Review, we discuss a systems genetics strategy, which we call gene module association study (GMAS), as a novel approach complementing genome-wide association studies (GWAS), to understand complex diseases by focusing on how genes work together in groups rather than singly. The first step is to characterize phenotypic differences among a genetically diverse population. The second step is to use gene expression microarray (or other high-throughput) data from the population to construct gene coexpression networks. Coexpression analysis typically groups 20 000 genes into 20 to 30 modules containing tens to hundreds of genes, whose aggregate behavior can be represented by the module’s “eigengene. ” The third step is to correlate expression patterns with phenotype, as in GWAS, only applied to eigengenes instead of Abstract The cardiac conduction system is a specialized tract of myocardial cells responsible for maintaining normal cardiac rhythm. Given its critical role in coordinating cardiac performance, a detailed analysis of the molecular mechanisms underlying conduction system formation should inform our understanding of arrhythmia pathophysiology and affect the development of novel therapeutic strategies. Historically, the ability to distinguish cells of the conduction system from neighboring working myocytes presented a major technical challenge for performing comprehensive mechanistic studies. Early lineage tracing experiments suggested that conduction cells derive from cardiomyocyte precursors, and these claims have been substantiated by using more contemporary approaches. However, regional specialization of conduction cells adds an additional layer of complexity to this system, and it appears that different components of the conduction system utilize unique modes of developmental formation. The identification of numerous transcription factors and their downstream target genes involved in regional differentiation of the conduction system has provided insight into how lineage commitment is achieved. Furthermore, by adopting cutting-edge genetic techniques in combination with sophisticated phenotyping ca-pabilities, investigators have made substantial progress in de-lineating the regulatory networks that orchestrate conduction system formation and their role in cardiac rhythm and physiol-ogy. This review describes the connectivity of these gene regulatory networks in cardiac conduction system development and discusses how they provide a foundation for understanding normal and pathological human cardiac rhythms. Abstract Mouse genetic engineering has revolutionized our understanding of the molecular and genetic basis of heart development and disease. This technology involves conditional tissue-spe-cific and temporal transgenic and gene targeting approaches, as well as introduction of polymorphisms into the mouse genome. These approaches are increasingly used to elucidate the genetic pathways underlying tissue homeostasis, physiology, and pathophysiology of adult heart. They have also led to the development of clinically relevant models of human cardiac diseases. Here, we review the technologies and their limitations in general and the cardiovascular research community in particular. demonstrate the versatility of Biotag system for studies of vascular biology in genetically engineered mice, providing a robust approach for multimodal in vivo imaging of genetic processes in the of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. The recent successful and safe completion of a phase 2 trial targeting Abstract This review reflects and expands on the contents of my presentation at the American Heart Association Scientific Sessions, 2011. “Decoding the cardiac message” refers to accumulating results from ongoing microRNA research that is altering longstanding concepts of the mechanisms for, and consequences of, messenger RNA (mRNA) regulation in the heart. First, I provide a brief historical perspective of the field of molecular genetics, touching on seminal research that paved the way for modern molecular cardiovascular research and helped establish the foundation for current concepts of mRNA regulation in the heart. I follow with some interesting details about the specific research that led to the discovery and appreciation of microRNAs as highly conserved pivotal regulators of RNA expression and translation. Finally, I provide a personal viewpoint as to how agnostic genome-wide techniques for measuring microRNAs, their mRNA targets, and their protein products can be applied in an integrated multisystems approach to uncover direct and indirect effects of microRNAs. Experimental designs integrating next-generation sequencing and global proteomics have the potential to address unanswered questions regarding microRNA–mRNA interactions in cardiac disease, how disease alters mRNA targeting by specific microRNAs, and how mutational and polymorphic nucleotide variation in microRNAs can affect end-organ function and stress response. Abstract The study of single gene disorders often provides insight for more complex human disease. Mutations in the genes encoding the dystrophin protein complex cause muscular dystrophy and cardiomyopathy by destabilizing the plasma membrane of skeletal myofibers and cardiomyocytes. In these diseases, that canonical transforming growth factor- β signaling contributes to heart and muscle dysfunction using a Drosophila model. Together, these studies demonstrate the value of using a genetically sensitized model to uncover pathways that regulate heart failure and muscle weakness. Abstract Atherosclerosis is a complex and heritable disease involving multiple cell types and the interactions of many different molecular pathways. The genetic and molecular mechanisms of atherosclerosis have, in part, been elucidated by mouse models; at least 100 different genes have been shown to influence atherosclerosis in mice. Importantly, unbiased genome-wide association studies have recently identified a number of novel loci robustly associated with atherosclerotic coronary artery disease. Here, we review the genetic data elucidated from mouse models of atherosclerosis, as well as significant associations for human coronary artery disease. Furthermore, we discuss in greater detail some of these novel human coronary artery disease loci. The combination of mouse and human genetics has the potential to identify and validate novel genes that influence atherosclerosis, some of which may be candi-dates for new therapeutic approaches. Abstract The nematode Caenorhabditis elegans has become established as a major experimental organism with applications to many biomedical research areas. The body wall muscle cells are a useful model for the study of human cardiomyocytes and their homologous structures and proteins. The ability to readily identify mutations affecting these proteins and structures in C elegans and to be able to rigorously characterize their genotypes and phenotypes at the cellular and molecular levels permits mechanistic studies of the responsible interactions relevant to the inherited human cardiomyopathies. Future work in C elegans muscle holds great promise in uncovering new mechanisms in the pathogenesis of these cardiac disorders. Abstract Patients vary in their responses to drug therapy, and some of that variability is genetically determined. This review outlines general approaches used to identify genetic variation that influences drug response. Examples from specific therapeutic areas are presented, such as cholesterol management, arrhythmias, heart failure, hypertension, warfarin anticoagulation, and antiplatelet agents. A brief view of potential pathways to implementation is presented. Abstract The fruit fly, Drosophila melanogaster, has been used to study genetics, development, and signaling for nearly a century, but only over the past few decades has this