scholarly journals A cis-regulatory-directed pipeline for the identification of genes involved in cardiac development and disease

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Hieu T. Nim ◽  
Louis Dang ◽  
Harshini Thiyagarajah ◽  
Daniel Bakopoulos ◽  
Michael See ◽  
...  
Keyword(s):  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Tissue ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Regulatory Element ◽  
Adult Mortality ◽  
Disease Genes ◽  
Novel Genes ◽  
Specific Expression

Abstract Background Congenital heart diseases are the major cause of death in newborns, but the genetic etiology of this developmental disorder is not fully known. The conventional approach to identify the disease-causing genes focuses on screening genes that display heart-specific expression during development. However, this approach would have discounted genes that are expressed widely in other tissues but may play critical roles in heart development. Results We report an efficient pipeline of genome-wide gene discovery based on the identification of a cardiac-specific cis-regulatory element signature that points to candidate genes involved in heart development and congenital heart disease. With this pipeline, we retrieve 76% of the known cardiac developmental genes and predict 35 novel genes that previously had no known connectivity to heart development. Functional validation of these novel cardiac genes by RNAi-mediated knockdown of the conserved orthologs in Drosophila cardiac tissue reveals that disrupting the activity of 71% of these genes leads to adult mortality. Among these genes, RpL14, RpS24, and Rpn8 are associated with heart phenotypes. Conclusions Our pipeline has enabled the discovery of novel genes with roles in heart development. This workflow, which relies on screening for non-coding cis-regulatory signatures, is amenable for identifying developmental and disease genes for an organ without constraining to genes that are expressed exclusively in the organ of interest.

Congenital Heart Diseases and Biotechnology: Connecting by Connexin

2014 ◽  
Vol 995 ◽  
pp. 85-112
Author(s):  
Naznin Sultana ◽  
Nobuhiro Nakamura ◽  
Shigehisa Hirose ◽  
Koichi Kutsuzawa ◽  
Toshihiro Akaike ◽  
...  
Keyword(s):  
Gap Junction ◽  
Heart Development ◽  
Congenital Heart ◽  
Cellular Proliferation ◽  
Cardiac Tissue ◽  
Heart Diseases ◽  
Heart Defects ◽  
Normal Function ◽  
Congenital Heart Diseases ◽  
Developmental Defects

Heart development is a precisely harmonized process of cellular proliferation, migration, differentiation, and integrated morphogenetic interactions, and therefore it is extremely vulnerable to developmental defects that cause congenital heart diseases (CHD). One of the major causes of CHD has been shown to be the mutations in key cardiac channel-forming proteins namely, connexins (Cxs). Cxs are tetra-spanning transmembrane proteins that form gap junction channels and hemichannels on cellular membrane. They allow passage of small molecules or ions between adjacent cells or between cells and the extracellular environment. Studies have revealed that the spatiotemporal expression of Cxs mainly, Cx31.9, Cx40, Cx43, and Cx45 is essentially involved in early developmental events, morphogenetic transformations, maturation, and functional significance of heart. Our lab and others have shown that mutations in gap junction proteins could result in impaired trafficking, misfolding, and improper channel function of these proteins. It has also been shown that differential expressions of cardiac Cxs are associated with pathophysiological conditions of heart. Collectively, these conditions are coupled with abrogated or modified functionality of relevant channels in cardiac tissue, which are associated with many pathological situations, including CHD. Since CHD are a major cause of morbidity, therefore recovery of such kind of heart defects associated with Cxs is extremely important but remains highly challenging. In this review, we will summarize the role of Cxs in development, morphogenesis, maturation, normal function, and pathology of heart, and propose possible bioengineering techniques to recover defects in cardiac tissues related to the modified functions of Cxs.

scholarly journals Abnormal Cardiac Development in the Absence of Heart Glycogen

2004 ◽  
Vol 24 (16) ◽  
pp. 7179-7187 ◽  
Author(s):  
Bartholomew A. Pederson ◽  
Hanying Chen ◽  
Jill M. Schroeder ◽  
Weinian Shou ◽  
Anna A. DePaoli-Roach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Cardiac Muscle ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Mendelian Inheritance ◽  
And Function ◽  
Impaired Cardiac Function

ABSTRACT Glycogen serves as a repository of glucose in many mammalian tissues. Mice lacking this glucose reserve in muscle, heart, and several other tissues were generated by disruption of the GYS1 gene, which encodes an isoform of glycogen synthase. Crossing mice heterozygous for the GYS1 disruption resulted in a significant underrepresentation of GYS1-null mice in the offspring. Timed matings established that Mendelian inheritance was followed for up to 18.5 days postcoitum (dpc) and that ∼90% of GYS1-null animals died soon after birth due to impaired cardiac function. Defects in cardiac development began between 11.5 and 14.5 dpc. At 18.5 dpc, the hearts were significantly smaller, with reduced ventricular chamber size and enlarged atria. Consistent with impaired cardiac function, edema, pooling of blood, and hemorrhagic liver were seen. Glycogen synthase and glycogen were undetectable in cardiac muscle and skeletal muscle from the surviving null mice, and the hearts showed normal morphology and function. Congenital heart disease is one of the most common birth defects in humans, at up to 1 in 50 live births. The results provide the first direct evidence that the ability to synthesize glycogen in cardiac muscle is critical for normal heart development and hence that its impairment could be a significant contributor to congenital heart defects.

scholarly journals Drosophila Heart as a Model for Cardiac Development and Diseases

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3078
Author(s):  
Anissa Souidi ◽  
Krzysztof Jagla
Keyword(s):  
Cardiac Dysfunction ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Heart Defects ◽  
Fruit Fly ◽  
Model System ◽  
Fast Imaging

The Drosophila heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly heart displays several developmental and functional similarities to the vertebrate heart and, as we discuss here, represents an attractive model system for dissecting mechanisms of cardiac aging and heart failure and identifying genes causing congenital heart diseases. Fast imaging technologies allow for the characterization of heartbeat parameters in the adult fly and there is growing evidence that cardiac dysfunction in human diseases could be reproduced and analyzed in Drosophila, as discussed here for heart defects associated with the myotonic dystrophy type 1. Overall, the power of genetics and unsuspected conservation of genes and pathways puts Drosophila at the heart of fundamental and applied cardiac research.

scholarly journals ISCA1 Deficiency Induces Iron Metabolism Disorder and Myocardial Oncosis in Rat

2021 ◽  
Author(s):  
Yahao Ling ◽  
Xinlan Yang ◽  
Xu Zhang ◽  
Feifei Guan ◽  
Xiaolong Qi ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Iron Metabolism ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Pathological Process ◽  
Metabolism Disorder ◽  
Abnormal Metabolism ◽  
Validation Experiments

Abstract The effects of multiple mitochondrial dysfunction (MMD) on heart, a highly mitochondria-dependent tissue, is still unclear. This study was the first to verify the effect of ISCA1 gene deficiency, which has been shown to cause multiple mitochondrial dysfunction syndromes type 5 (MMDS5), on cardiac development in vivo, that is cardiomyocytes suffer from energy shortage due to abnormal metabolism of iron ion, which leads to oncosis and eventually HF and body death. Subsequently, we determine a new interacting molecule for ISCA1, six-transmembrane epithelial antigen of prostate 3 (STEAP3), which acts as a reductase in the reduction of Fe3+ to Fe2+. Forward and reverse validation experiments demonstrated that STEAP3 plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching of clinical therapeutic targets.

scholarly journals Epigenetic Regulation of Cardiac Neural Crest Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Shun Yan ◽  
Jin Lu ◽  
Kai Jiao
Keyword(s):  
Neural Crest ◽  
Epigenetic Regulation ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Heart Defects ◽  
Neural Crest Cells ◽  
Abnormal Development ◽  
Cardiac Neural Crest ◽  
Epigenetic Regulators

The cardiac neural crest cells (cNCCs) is a transient, migratory cell population that contribute to the formation of major arteries and the septa and valves of the heart. Abnormal development of cNCCs leads to a spectrum of congenital heart defects that mainly affect the outflow region of the hearts. Signaling molecules and transcription factors are the best studied regulatory events controlling cNCC development. In recent years, however, accumulated evidence supports that epigenetic regulation also plays an important role in cNCC development. Here, we summarize the functions of epigenetic regulators during cNCC development as well as cNCC related cardiovascular defects. These factors include ATP-dependent chromatin remodeling factors, histone modifiers and DNA methylation modulators. In many cases, mutations in the genes encoding these factors are known to cause inborn heart diseases. A better understanding of epigenetic regulators, their activities and their roles during heart development will ultimately contribute to the development of new clinical applications for patients with congenital heart disease.

From molecular mechanisms of cardiac development to genetic substrate of congenital heart diseases

2010 ◽  
Vol 6 (3) ◽  
pp. 373-393 ◽  
Author(s):  
Antonella Cecchetto ◽  
Alessandra Rampazzo ◽  
Annalisa Angelini ◽  
Lucia Dal Bianco ◽  
Massimo Padalino ◽  
...  
Keyword(s):  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Congenital Heart Diseases

scholarly journals Comparative DNA methylation and gene expression analysis identifies novel genes for structural congenital heart diseases

2016 ◽  
Vol 112 (1) ◽  
pp. 464-477 ◽  
Author(s):  
Marcel Grunert ◽  
Cornelia Dorn ◽  
Huanhuan Cui ◽  
Ilona Dunkel ◽  
Kerstin Schulz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Expression Analysis ◽  
Congenital Heart ◽  
Gene Expression Analysis ◽  
Heart Diseases ◽  
Congenital Heart Diseases ◽  
Novel Genes

A novel, tissue-restricted zinc finger protein (HF-1b) binds to the cardiac regulatory element (HF-1b/MEF-2) in the rat myosin light-chain 2 gene

1993 ◽  
Vol 13 (7) ◽  
pp. 4432-4444
Author(s):  
H Zhu ◽  
V T Nguyen ◽  
A B Brown ◽  
A Pourhosseini ◽  
A V Garcia ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Zinc Finger ◽  
Cardiac Tissue ◽  
Zinc Finger Protein ◽  
Regulatory Element ◽  
Binding Activity ◽  
Cardiac Muscle Cells ◽  
Specific Expression ◽  
Isolation And Characterization ◽  
Finger Protein

The AT-rich element MEF-2 plays an important role in the maintenance of the muscle-specific expression of a number of cardiac and skeletal muscle genes. In the MLC-2 gene, an AT-rich element (HF-1b) which contains a consensus MEF-2 site is required for cardiac tissue-specific expression. The present study reports the isolation and characterization of a cDNA which encodes a novel C2H2 zinc finger (HF-1b) that binds in a sequence-specific manner to the HF-1b/MEF-2 site in the MLC-2 promoter. A number of independent criteria suggest that this HF-1b zinc finger protein is a component of the endogenous HF-1b/MEF-2 binding activity in cardiac muscle cells and that it can serve as a transcriptional activator of the MLC-2 promoter in transient assays. These studies suggest that, in addition to the previously reported RSRF proteins, structurally divergent transcriptional factors can bind to MEF-2-like sites in muscle promoters. These results underscore the complexity of the regulation of the muscle gene program via these AT-rich elements in cardiac and skeletal muscle.

Abstract MP174: Cardiomyocyte-specific Deletion of Parathyroid Hormone Receptor 1 During Development Leads to Left Ventricular Hypoplasia

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Desiree Leach ◽  
Ryan Jorgensen ◽  
Jayne Wolfe ◽  
Lisa D Wilsbacher
Keyword(s):  
Parathyroid Hormone ◽  
Heart Development ◽  
Hormone Receptor ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Left Ventricular ◽  
Mutant Mice ◽  
Camp Production ◽  
Parathyroid Hormone Receptor ◽  
Specific Deletion

Congenital heart defects occur in approximately 1% of all births and signify the most common human birth defects. Our lab previously demonstrated that cardiomyocyte specific deletion of Sphingosine 1-Phosphate Receptor 1 (S1P 1 ), a G protein-coupled receptor (GPCR) that couples exclusively to Gαi, leads to ventricular noncompaction in mice. Gαs- and Gαi-coupled GPCRs activate and inhibit adenylate cyclase, respectively, thereby regulating cAMP production. These GPCRs play important roles in adult cardiac health and disease, but their contributions to heart development are not well understood. We hypothesized that tight regulation of cAMP via Gαs- and Gαi-coupled GPCRs is a critical determinant of cardiomyocyte maturation and cardiac development. Here, we report that Parathyroid Hormone Receptor 1 (Pth1r) which couples to Gαs, is a mediator of cardiomyocyte maturation. Using mice with a Cre allele in the myosin light chain 2a locus ( Myl7 Cre/+, also known as Mlc2a Cre/+ ), we found that cardiomyocyte-specific deletion of Pth1r during development led to reduced postnatal survival. Hearts collected from surviving Pth1r cardiomyocyte mutant mice displayed left ventricular (LV) hypoplasia, and fetal cardiac genes Nppa (natriuretic peptide A) and β myosin heavy chain (Myh7) were upregulated in the hearts of surviving mutants. At 14.5 days post coitus (dpc) and 18.5 dpc, Pth1r cardiomyocyte mutant mice also showed LV hypoplasia. Furthermore, we observed decreased cardiomyocyte proliferation in Pth1r cardiomyocyte mutant hearts during development. Isolated cardiomyocytes from C57BL/6 wild-type embryos showed increased cAMP production after stimulation of Pth1r; Pth1r-dependent cAMP increases were inhibited by activation of S1P 1 . Overall, our results indicate a critical role for Pth1r signaling during heart development and suggest that cAMP levels must be tightly controlled in cardiomyocytes for normal cardiac development. LV hypoplasia is one of the key features of hypoplastic left heart syndrome (HLHS), one of the most severe forms of congenital heart disease; these studies may provide new approaches for the study and treatment of LV hypoplasia and HLHS.

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