scholarly journals Nkx2-5 defines distinct scaffold and recruitment phases during formation of the murine cardiac Purkinje fiber network

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Caroline Choquet ◽  
Robert G. Kelly ◽  
Lucile Miquerol
Keyword(s):  
Transcription Factor ◽  
Electrical Activity ◽  
Cell Fate ◽  
Clonal Analysis ◽  
Conduction System ◽  
Purkinje Fiber ◽  
Fate Mapping ◽  
Fiber Network ◽  
Apply Genetic ◽  
Ventricular Conduction

Abstract The ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. Here, we apply genetic fate mapping and temporal clonal analysis to identify murine cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.

scholarly journals Nkx2-5 defines distinct scaffold and recruitment phases during formation of the cardiac Purkinje fiber network

2020 ◽  
Author(s):  
Caroline Choquet ◽  
Robert G. Kelly ◽  
Lucile Miquerol
Keyword(s):  
Transcription Factor ◽  
Electrical Activity ◽  
Cell Fate ◽  
Clonal Analysis ◽  
Conduction System ◽  
Purkinje Fiber ◽  
Fate Mapping ◽  
Fiber Network ◽  
Apply Genetic ◽  
Ventricular Conduction

AbstractThe ventricular conduction system coordinates heartbeats by rapid propagation of electrical activity through the Purkinje fiber (PF) network. PFs share common progenitors with contractile cardiomyocytes, yet the mechanisms of segregation and network morphogenesis are poorly understood. In this study, we apply genetic fate mapping and temporal clonal analysis to identify cardiomyocytes committed to the PF lineage as early as E7.5. We find that a polyclonal PF network emerges by progressive recruitment of conductive precursors to this scaffold from a pool of bipotent progenitors. At late fetal stages, the segregation of conductive cells increases during a phase of rapid recruitment to build the definitive PF network through a non-cell autonomous mechanism. We also show that PF differentiation is impaired in Nkx2-5 haploinsufficient embryos leading to failure to extend the scaffold. In particular, late fetal recruitment fails, resulting in PF hypoplasia and persistence of bipotent progenitors. Our results identify how transcription factor dosage regulates cell fate divergence during distinct phases of PF network morphogenesis.

scholarly journals New Insights into the Development and Morphogenesis of the Cardiac Purkinje Fiber Network: Linking Architecture and Function

2021 ◽  
Vol 8 (8) ◽  
pp. 95
Author(s):  
Caroline Choquet ◽  
Lucie Boulgakoff ◽  
Robert G. Kelly ◽  
Lucile Miquerol
Keyword(s):  
Cardiac Conduction ◽  
Purkinje Fiber ◽  
Primary Ring ◽  
Fiber Network ◽  
Conduction Disturbances ◽  
Function Relationship ◽  
And Function ◽  
Cardiac Transcription Factors ◽  
Ventricular Conduction ◽  
Ventricular Trabeculae

The rapid propagation of electrical activity through the ventricular conduction system (VCS) controls spatiotemporal contraction of the ventricles. Cardiac conduction defects or arrhythmias in humans are often associated with mutations in key cardiac transcription factors that have been shown to play important roles in VCS morphogenesis in mice. Understanding of the mechanisms of VCS development is thus crucial to decipher the etiology of conduction disturbances in adults. During embryogenesis, the VCS, consisting of the His bundle, bundle branches, and the distal Purkinje network, originates from two independent progenitor populations in the primary ring and the ventricular trabeculae. Differentiation into fast-conducting cardiomyocytes occurs progressively as ventricles develop to form a unique electrical pathway at late fetal stages. The objectives of this review are to highlight the structure–function relationship between VCS morphogenesis and conduction defects and to discuss recent data on the origin and development of the VCS with a focus on the distal Purkinje fiber network.

Abstract 17134: Variation Within a Left Ventricle-Specific Hand1 Enhancer Impairs Gata Transcription Factor Binding and Disrupts Ventricular Conduction System Development

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Joshua W Vincentz ◽  
Beth A Firulli ◽  
Kevin P Toolan ◽  
Dan E Arking ◽  
Nona Sotoodehnia ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Left Ventricle ◽  
Regulatory Element ◽  
Conduction System ◽  
Genome Wide Association ◽  
Regulatory Activity ◽  
Genome Wide ◽  
Gata Transcription Factor ◽  
Qrs Prolongation ◽  
Ventricular Conduction

The ventricular conduction system (VCS), composed of the His bundle, the left and right bundle branches, and the Purkinje fiber network, rapidly propagates electrical impulses through the ventricles to coordinate chamber contraction. An ECG depicts VCS-mediated ventricular depolarization as the QRS interval. Disorders of the VCS may manifest as arrhythmias, and are associated with increased risk of sudden cardiac death and overall mortality. The genetic and developmental mechanisms underlying VCS dysfunction are poorly understood. Genome-wide association studies have identified multiple single nucleotide polymorphisms (SNPs) associated with VCS arrhythmias. A majority of these SNPs occur outside of coding domains, within intergenic or intronic regions. We hypothesize that such pathogenic SNPs may impact VCS development and function by altering the expression of critical genes. Two intergenic SNPs associated with QRS prolongation occur near the bHLH cardiac transcription factor HAND1 . We have identified a left ventricle (LV) enhancer, located between these two SNPs, that is necessary and sufficient for LV cis -regulatory activity. Two evolutionarily conserved GATA transcription factor consensus-binding sites within this enhancer are bound by GATA4 and necessary for cis -regulatory activity. CRISPR-mediated deletion of this enhancer dramatically reduced Hand1 expression solely within the LV. Mice homozygous for this deleted enhancer displayed dysregulated LV gene expression, morphologically abnormal His bundles and left bundle branches, and a VCS phenotype consistent with right bundle branch block. Genome-wide association analyses of human patients with QRS prolongation revealed additional, linked SNPs, one of which overlaps with a critical GATA cis -regulatory element within the LV-specific Hand1 enhancer. This SNP disrupts GATA4 binding. Ongoing studies of mice that genetically mimic these minor SNP variants will assess reduced Hand1 expression and impaired VCS function. We conclude that a LV-specific Hand1 enhancer is necessary for VCS development and a SNP associated with QRS prolongation directly influences GATA4 binding to a critical cis -regulatory element within this enhancer.

scholarly journals H019 Clonal analysis of the origin of the ventricular conduction system

2009 ◽  
Vol 102 ◽  
pp. S78
Author(s):  
L. Miquerol ◽  
N. Moreno ◽  
L. Dupays ◽  
S. Meilhac ◽  
M. Buckingham ◽  
...  
Keyword(s):  
Clonal Analysis ◽  
Conduction System ◽  
Ventricular Conduction

scholarly journals The EGL-13 SOX Domain Transcription Factor Affects the Uterine Cell Lineages in Caenorhabditis elegans

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1623-1628
Author(s):  
Hediye Nese Cinar ◽  
Keri L Richards ◽  
Kavita S Oommen ◽  
Anna P Newman
Keyword(s):  
Transcription Factor ◽  
Cell Division ◽  
Caenorhabditis Elegans ◽  
Cell Fate ◽  
Cell Lineages

Abstract We isolated egl-13 mutants in which the cells of the Caenorhabditis elegans uterus initially appeared to develop normally but then underwent an extra round of cell division. The data suggest that egl-13 is required for maintenance of the cell fate.

scholarly journals NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

2021 ◽  
Vol 22 (13) ◽  
pp. 6713
Author(s):  
Romana Bohuslavova ◽  
Ondrej Smolik ◽  
Jessica Malfatti ◽  
Zuzana Berkova ◽  
Zaneta Novakova ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Cell Mass ◽  
Neonatal Diabetes ◽  
Diabetes Research ◽  
Pancreas Development ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Islet Cell ◽  
Endocrine Differentiation

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.

scholarly journals Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Vishwanie S. Budhram-Mahadeo ◽  
Matthew R. Solomons ◽  
Eeshan A. O. Mahadeo-Heads
Keyword(s):  
Transcription Factor ◽  
Cardiovascular Diseases ◽  
Cell Fate ◽  
Target Genes ◽  
Cardiovascular Responses ◽  
Normal Function ◽  
Valuable Insight ◽  
Metabolic Dysfunction ◽  
Pathological Changes ◽  
Cardiac Responses

AbstractMetabolic and cardiovascular diseases are highly prevalent and chronic conditions that are closely linked by complex molecular and pathological changes. Such adverse effects often arise from changes in the expression of genes that control essential cellular functions, but the factors that drive such effects are not fully understood. Since tissue-specific transcription factors control the expression of multiple genes, which affect cell fate under different conditions, then identifying such regulators can provide valuable insight into the molecular basis of such diseases. This review explores emerging evidence that supports novel and important roles for the POU4F2/Brn-3b transcription factor (TF) in controlling cellular genes that regulate cardiometabolic function. Brn-3b is expressed in insulin-responsive metabolic tissues (e.g. skeletal muscle and adipose tissue) and is important for normal function because constitutive Brn-3b-knockout (KO) mice develop profound metabolic dysfunction (hyperglycaemia; insulin resistance). Brn-3b is highly expressed in the developing hearts, with lower levels in adult hearts. However, Brn-3b is re-expressed in adult cardiomyocytes following haemodynamic stress or injury and is necessary for adaptive cardiac responses, particularly in male hearts, because male Brn-3b KO mice develop adverse remodelling and reduced cardiac function. As a TF, Brn-3b regulates the expression of multiple target genes, including GLUT4, GSK3β, sonic hedgehog (SHH), cyclin D1 and CDK4, which have known functions in controlling metabolic processes but also participate in cardiac responses to stress or injury. Therefore, loss of Brn-3b and the resultant alterations in the expression of such genes could potentially provide the link between metabolic dysfunctions with adverse cardiovascular responses, which is seen in Brn-3b KO mutants. Since the loss of Brn-3b is associated with obesity, type II diabetes (T2DM) and altered cardiac responses to stress, this regulator may provide a new and important link for understanding how pathological changes arise in such endemic diseases.

scholarly journals Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kylie Hin-Man Mak ◽  
Yuk Man Lam ◽  
Ray Kit Ng
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Cell Fate ◽  
Histone Demethylase ◽  
Gene Promoters ◽  
Transcriptional Program ◽  
Binding Motifs ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Trophoblast Stem Cell

AbstractTrophoblast stem cell (TSC) is crucial to the formation of placenta in mammals. Histone demethylase JMJD2 (also known as KDM4) family proteins have been previously shown to support self-renewal and differentiation of stem cells. However, their roles in the context of the trophoblast lineage remain unclear. Here, we find that knockdown of Jmjd2b resulted in differentiation of TSCs, suggesting an indispensable role of JMJD2B/KDM4B in maintaining the stemness. Through the integration of transcriptome and ChIP-seq profiling data, we show that JMJD2B is associated with a loss of H3K36me3 in a subset of embryonic lineage genes which are marked by H3K9me3 for stable repression. By characterizing the JMJD2B binding motifs and other transcription factor binding datasets, we discover that JMJD2B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1. The JMJD2B–TFAP2C–LSD1 complex predominantly occupies active gene promoters, whereas the TFAP2C–LSD1 complex is located at putative enhancers, suggesting that these proteins mediate enhancer–promoter interaction for gene regulation. We conclude that JMJD2B is vital to the TSC transcriptional program and safeguards the trophoblast cell fate via distinctive protein interactors and epigenetic targets.

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