scholarly journals Histone Lysine Methyltransferase SETD2 Regulates Coronary Vascular Development in Embryonic Mouse Hearts

2021 ◽  
Vol 9 ◽  
Author(s):  
Fengling Chen ◽  
Jiewen Chen ◽  
Hong Wang ◽  
Huayuan Tang ◽  
Lei Huang ◽  
...  
Keyword(s):  
Heart Development ◽  
Heart Defects ◽  
Critical Role ◽  
Gene Mutations ◽  
Mouse Heart ◽  
Primary Role ◽  
Structural Variations ◽  
Embryonic Mouse ◽  
Cardiac Progenitors ◽  
Histone Lysine

Congenital heart defects are the most common birth defect and have a clear genetic component, yet genomic structural variations or gene mutations account for only a third of the cases. Epigenomic dynamics during human heart organogenesis thus may play a critical role in regulating heart development. However, it is unclear how histone mark H3K36me3 acts on heart development. Here we report that histone-lysine N-methyltransferase SETD2, an H3K36me3 methyltransferase, is a crucial regulator of the mouse heart epigenome. Setd2 is highly expressed in embryonic stages and accounts for a predominate role of H3K36me3 in the heart. Loss of Setd2 in cardiac progenitors results in obvious coronary vascular defects and ventricular non-compaction, leading to fetus lethality in mid-gestation, without affecting peripheral blood vessel, yolk sac, and placenta formation. Furthermore, deletion of Setd2 dramatically decreased H3K36me3 level and impacted the transcriptional landscape of key cardiac-related genes, including Rspo3 and Flrt2. Taken together, our results strongly suggest that SETD2 plays a primary role in H3K36me3 and is critical for coronary vascular formation and heart development in mice.

scholarly journals Embryonic Mouse Cardiodynamic OCT Imaging

2020 ◽  
Vol 7 (4) ◽  
pp. 42
Author(s):  
Andrew L. Lopez ◽  
Shang Wang ◽  
Irina V. Larina
Keyword(s):  
Blood Flow ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Cellular Level ◽  
Mouse Heart ◽  
Embryonic Mouse ◽  
Insight Into

The embryonic heart is an active and developing organ. Genetic studies in mouse models have generated great insight into normal heart development and congenital heart defects, and suggest mechanical forces such as heart contraction and blood flow to be implicated in cardiogenesis and disease. To explore this relationship and investigate the interplay between biomechanical forces and cardiac development, live dynamic cardiac imaging is essential. Cardiodynamic imaging with optical coherence tomography (OCT) is proving to be a unique approach to functional analysis of the embryonic mouse heart. Its compatibility with live culture systems, reagent-free contrast, cellular level resolution, and millimeter scale imaging depth make it capable of imaging the heart volumetrically and providing spatially resolved information on heart wall dynamics and blood flow. Here, we review the progress made in mouse embryonic cardiodynamic imaging with OCT, highlighting leaps in technology to overcome limitations in resolution and acquisition speed. We describe state-of-the-art functional OCT methods such as Doppler OCT and OCT angiography for blood flow imaging and quantification in the beating heart. As OCT is a continuously developing technology, we provide insight into the future developments of this area, toward the investigation of normal cardiogenesis and congenital heart defects.

Abstract 82: Wnt11 Regulates Chamber Specific Neonatal Cardiomyocyte Proliferation During Perinatal Circulatory Transition

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Marlin Touma ◽  
Xuedong Kang ◽  
Fuying Gao ◽  
Yan Zhao ◽  
Reshma Biniwale ◽  
...  
Keyword(s):  
Heart Defects ◽  
Critical Role ◽  
Newborn Infants ◽  
R Package ◽  
Maturation Stage ◽  
Specific Gene ◽  
Mouse Heart ◽  
Cardiomyocyte Proliferation ◽  
Loss Of Function ◽  
Myocyte Proliferation

Background: Fetal to neonatal transition of heart involves major changes in cardiomyocytes (CMC) including proliferative capacity. However, the chamber specific CMC proliferation programs of remain poorly understood. Elucidating the mechanisms involved is critical to develop chamber specific therapies for newborn infants with single ventricle physiology and other congenital heart defects (CHDs). Methods: Transcriptomes of mouse left ventricle (LV) and right ventricle (RV) were analyzed by RNA-seq at postnatal days 0 (P0), P3 and P7. R package and Ingenuity suite were used for weighted gene co-expression network analysis (WGCNA) and gene ontology studies. Mechanistic analysis was conducted using gain and loss of function approaches. Results: Mouse neonatal cardiac transcriptome was mostly affected by developmental stage. WGCNA revealed 5 LV and 8 RV modules that were significantly correlated with maturation stage and highly preserved between both ventricles at P0 and P7. In contrast, P3 specific gene modules exhibited the largest chamber specific variations in cell signaling, involving proliferation in LV and Wnt signaling molecules, including Wnt11, in RV. Importantly, Wnt11 expression significantly decreased in cyanotic CHDs phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Notably, Perinatal hypoxia treatment in mice suppressed Wnt11 expression, induced CMC proliferation, downregulated Rb1 expression and enhanced Rb1 phosphorylation more robustly in RV vs. LV. Remarkably, Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse heart and reduced Rb1 expression and phosphorylation in primary neonatal CMC. Importantly, downregulated Wnt11 in hypoxemic TOF infantile heart was also associated with Rb1 suppression and inversely correlated with proliferation marker Plk1 in human. Conclusion: Using integrated systems genomic and functional biology analyses of perinatal cardiac transcriptome, we revealed a previously uncharacterized function for Wnt11 in chamber specific growth and cyanotic CHD. Reduction of Wnt11 expression by hypoxia plays a critical role in neonatal CMC proliferation via modulating Rb1 expression and activity.

scholarly journals Hey2 restricts cardiac progenitor addition to the developing heart

2017 ◽  
Author(s):  
Natalie Gibb ◽  
Savo Lazic ◽  
Ashish R. Deshwar ◽  
Xuefei Yuan ◽  
Michael D. Wilson ◽  
...  
Keyword(s):  
Heart Development ◽  
Heart Defects ◽  
Myocardial Cell ◽  
Cell Number ◽  
Tube Formation ◽  
Heart Tube ◽  
Cardiac Progenitors ◽  
Developing Heart ◽  
Heart Field ◽  
A Cell

ABSTRACTA key event in vertebrate heart development is the timely addition of second heart field (SHF) progenitor cells to the poles of the heart tube. This accretion process must occur to the proper extent to prevent a spectrum of congenital heart defects (CHDs). However, the factors that regulate this critical process are poorly understood. Here we demonstrate that Hey2, a bHLH transcriptional repressor, restricts SHF progenitor accretion to the zebrafish heart. hey2 expression demarcated a distinct domain within the cardiac progenitor population. In the absence of Hey2 function an increase in myocardial cell number and SHF progenitors was observed. We found that Hey2 limited proliferation of SHF-derived cardiomyocytes in a cell-autonomous manner, prior to heart tube formation, and further restricted the developmental window over which SHF progenitors were deployed to the heart. Taken together, our data suggests a role for Hey2 in controlling the proliferative capacity and cardiac contribution of late-differentiating cardiac progenitors.

Abstract P158: MicroRNA-22 Modulates Cardiac Gene Expression and Controls Compensation to Hemodynamic Stress in Mice

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Priyatansh Gurha ◽  
Robert Kelm ◽  
Mark Entman ◽  
George Taffet ◽  
Allan Bradley ◽  
...  
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Cardiac Contractility ◽  
Pressure Overload ◽  
Mouse Heart ◽  
Primary Role ◽  
Translational Repressor ◽  
Muscle Gene Expression ◽  
Hemodynamic Stress

Recent evidence suggests that miRNAs play an important role in cardiac morphogenesis and pathophyiology of heart failure. To explore the role of miR-22 in the mouse heart physiology, we generated miR-22 null (KO) mice. Although, miR-22 KO mice showed normal cardiac structure and function at baseline, these mice are sensitized to maladaptive remodeling (cardiac dilation) and decompensation in response to pressure overload by transverse aortic constrictions (TAC) stimulation. Genome-wide molecular analysis of KO hearts revealed attenuated expression of numerous CarG-dependent genes encoding proteins that reside at the sarcomeric Z-disc (including Myh7, Acta1, Mlp, Melusin, MyoZ2) indicating that miR-22 is required for optimum muscle gene expression. Alterations in sarcomeric gene expression is especially interesting as this suggests a primary role of miR-22 in controlling cardiac contractility and adaptation to stress. Targetomics analysis revealed that mechanistically this effect could be modulated in part by miR-22 target PURB (Purine Rich element binding protein B), a transcriptional/translational repressor. In conclusion we define a critical role of miR-22 in cardiac adaptation to hemodynamic stress. Furthermore, these data provides a previously unseen essential molecular mechanism that underlies homeostatic control of sarcomeric protein expression in the heart.

Yap is required for scar formation but not myocyte proliferation during heart regeneration in zebrafish

2018 ◽  
Vol 115 (3) ◽  
pp. 570-577 ◽  
Author(s):  
Michael A Flinn ◽  
Brooke E Jeffery ◽  
Caitlin C O’Meara ◽  
Brian A Link
Keyword(s):  
Heart Development ◽  
Critical Role ◽  
Scar Formation ◽  
Cardiac Cells ◽  
Mouse Heart ◽  
Heart Regeneration ◽  
Post Injury ◽  
Myocyte Proliferation ◽  
The Impact ◽  
Zebrafish Heart

Abstract Aims The Hippo signalling pathway regulates multiple cellular processes during organ development and maintenance by modulating activity of the transcriptional cofactor Yap. Core components of this pathway are required for neonatal mouse heart regeneration, however, investigations to date have typically focused on expression and activity in cardiomyocytes. Due to the regenerative capacity of zebrafish and the fact that global loss of Yap is not fully embryonic lethal in zebrafish, we leveraged a yap null mutant to investigate the impact of constitutive Yap deletion during zebrafish heart regeneration. Methods and results Following cryoinjury in adult hearts, myocyte proliferation was not decreased in yap mutants, contrary to expectations based on mouse data. Experiments in larval zebrafish (Danio rerio) revealed that deletion of either Yap or Taz had a modest effect on heart growth, reducing gross organ size, while their combined deletion was synergistic; thus, Yap and Taz share some overlapping roles in zebrafish heart development. Surprisingly, adult yap mutants exhibited decreased collagen composition at 7 days post-injury, suggesting a critical role for Yap in scar formation during heart regeneration. siRNA-mediated Yap knockdown in primary rat (Rattus norvegicus) cardiac cells revealed a fibroblast-specific role for Yap in controlling the expression of cytoskeletal and myofibroblast activation genes, as well as pro-inflammatory cyto/chemokines. Corroborating these RNAseq data, we observed increased macrophage infiltration in the scars of yap mutants at 7 days post-injury. Conclusion These results suggest that Yap deletion has minimal effect on myocyte proliferation in adults, but significantly influences scar formation and immune cell infiltration during zebrafish heart regeneration. Collectively, these data suggest an unexpected role for Yap in matrix formation and macrophage recruitment during heart regeneration.

scholarly journals From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

2021 ◽  
Vol 8 (2) ◽  
pp. 17
Author(s):  
Cassie L. Kemmler ◽  
Fréderike W. Riemslagh ◽  
Hannah R. Moran ◽  
Christian Mosimann
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Zebrafish Model ◽  
Lateral Plate ◽  
Cardiac Progenitors

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared with the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages central to cardiac development across vertebrates. The rapid, translucent development of zebrafish is amenable to in vivo imaging and genetic lineage tracing techniques, providing versatile tools to study heart field migration and myocardial progenitor addition and differentiation. Combining transgenic reporters with rapid genome engineering via CRISPR-Cas9 allows for functional testing of candidate genes associated with congenital heart defects and the discovery of molecular causes leading to observed phenotypes. Here, we summarize key insights gained through zebrafish studies into the early patterning of uncommitted lateral plate mesoderm into cardiac progenitors and their regulation. We review the central genetic mechanisms, available tools, and approaches for modeling congenital heart anomalies in the zebrafish as a representative vertebrate model.

Mutations in CHMP4C cause dilated cardiomyopathy via dysregulation of autophagy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N.W Zhou ◽  
L Tang ◽  
Y.Y Jiang ◽  
X.J Li ◽  
W.P Zhao ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Heart Development ◽  
Cardiac Development ◽  
Heart Function ◽  
Critical Role ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Clinical Genetic ◽  
Whole Exome

Abstract Background Gene mutations have been implicated in DCM. However, due to the difficulty of clinical genetic diagnosis, more causal genes potentially related to DCM remain to be discovered. Methods We screened for gene mutations in more than 400 cases from families with hereditary cardiovascular disease using whole-exome sequencing. Then we validated biological functions of CHMP4C mutations in zebrafish models. To further assess the mechanism of CHMP4C mutations, we evaluated the potential signaling pathway in the cells. Results We identification of CHMP4C variants that segregated with DCM variants in four families from a total of 411 families via whole-exome sequencing. We further validate the function of CHMP4C in heart function in zebrafish models and found that over-expression of CHMP4C variants in zebrafish resulted in cardiac malformation, pericardial edema and increased heart rate, consistent with CHMP4C mutation-associated findings in DCM patients. Furthermore, we found that mutations in CHMP4C impaired autophagy and activated apoptosis in HEK293T cells, suggesting that the molecular mechanism of CHMP4C is involved in heart development. Conclusions CHMP4C is a novel candidate gene for DCM and may play a critical role in cardiac development by regulating autophagy. Funding Acknowledgement Type of funding source: None

scholarly journals Characterization of a common progenitor pool of the epicardium and myocardium

Science ◽  
2021 ◽  
pp. eabb2986
Author(s):  
Richard C. V. Tyser ◽  
Ximena Ibarra-Soria ◽  
Katie McDole ◽  
Satish A. Jayaram ◽  
Jonathan Godwin ◽  
...  
Keyword(s):  
Cardiac Development ◽  
Cell Types ◽  
Trophic Factors ◽  
Mouse Heart ◽  
Genetic Lineage ◽  
Cardiac Cell ◽  
Embryonic Mouse ◽  
Cardiac Progenitors ◽  
Multiple Cell ◽  
Definition Of

The mammalian heart is derived from multiple cell lineages; however, our understanding of when and how the diverse cardiac cell types arise is limited. We mapped the origin of the embryonic mouse heart at single-cell resolution using a combination of transcriptomic, imaging, and genetic lineage labeling approaches. This provided a transcriptional and anatomic definition of cardiac progenitor types. Furthermore, it revealed a cardiac progenitor pool that is anatomically and transcriptionally distinct from currently known cardiac progenitors. Besides contributing to cardiomyocytes, these cells also represent the earliest progenitor of the epicardium, a source of trophic factors and cells during cardiac development and injury. This study provides detailed insights into the formation of early cardiac cell types, with particular relevance to the development of cell-based cardiac regenerative therapies.

scholarly journals HNF4a transcription is a target of trichloroethylene toxicity in the embryonic mouse heart

2020 ◽  
Vol 22 (3) ◽  
pp. 824-832
Author(s):  
Sheri Chen ◽  
Alejandro Lencinas ◽  
Martha Nunez ◽  
Ornella I. Selmin ◽  
Raymond B. Runyan
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Transcriptional Activity ◽  
Heart Defects ◽  
Central Component ◽  
Mouse Heart ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Embryonic Mouse ◽  
Hepatocyte Nuclear Factor 4

In exploration of congenital heart defects produced by TCE, Hepatocyte Nuclear Factor 4 alpha (HNF4a) transcriptional activity was identified as a central component.

scholarly journals Early patterning and specification of cardiac progenitors in gastrulating mesoderm

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
W Patrick Devine ◽  
Joshua D Wythe ◽  
Matthew George ◽  
Kazuko Koshiba-Takeuchi ◽  
Benoit G Bruneau
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Cardiac Regeneration ◽  
Cardiac Cells ◽  
Cardiac Progenitors ◽  
Compartment Boundary ◽  
Left And Right ◽  
Cellular Components

Mammalian heart development requires precise allocation of cardiac progenitors. The existence of a multipotent progenitor for all anatomic and cellular components of the heart has been predicted but its identity and contribution to the two cardiac progenitor ‘fields’ has remained undefined. Here we show, using clonal genetic fate mapping, that Mesp1+ cells in gastrulating mesoderm are rapidly specified into committed cardiac precursors fated for distinct anatomic regions of the heart. We identify Smarcd3 as a marker of early specified cardiac precursors and identify within these precursors a compartment boundary at the future junction of the left and right ventricles that arises prior to morphogenesis. Our studies define the timing and hierarchy of cardiac progenitor specification and demonstrate that the cellular and anatomical fate of mesoderm-derived cardiac cells is specified very early. These findings will be important to understand the basis of congenital heart defects and to derive cardiac regeneration strategies.

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