scholarly journals Decoding an organ regeneration switch by dissecting cardiac regeneration enhancers

Development ◽  
2020 ◽  
Vol 147 (24) ◽  
pp. dev194019
Author(s):  
Ian J. Begeman ◽  
Kwangdeok Shin ◽  
Daniel Osorio-Méndez ◽  
Andrew Kurth ◽  
Nutishia Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Regeneration ◽  
Cardiac Injury ◽  
Transcriptional Response ◽  
Cardiac Regeneration ◽  
Regulatory Elements ◽  
Heart Regeneration ◽  
New Paradigm ◽  
Closely Related Species ◽  
Organ Regeneration

ABSTRACTHeart regeneration in regeneration-competent organisms can be accomplished through the remodeling of gene expression in response to cardiac injury. This dynamic transcriptional response relies on the activities of tissue regeneration enhancer elements (TREEs); however, the mechanisms underlying TREEs are poorly understood. We dissected a cardiac regeneration enhancer in zebrafish to elucidate the mechanisms governing spatiotemporal gene expression during heart regeneration. Cardiac lepb regeneration enhancer (cLEN) exhibits dynamic, regeneration-dependent activity in the heart. We found that multiple injury-activated regulatory elements are distributed throughout the enhancer region. This analysis also revealed that cardiac regeneration enhancers are not only activated by injury, but surprisingly, they are also actively repressed in the absence of injury. Our data identified a short (22 bp) DNA element containing a key repressive element. Comparative analysis across Danio species indicated that the repressive element is conserved in closely related species. The repression mechanism is not operational during embryogenesis and emerges when the heart begins to mature. Incorporating both activation and repression components into the mechanism of tissue regeneration constitutes a new paradigm that might be extrapolated to other regeneration scenarios.

scholarly journals Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration

2021 ◽  
Author(s):  
Yingxi Cao ◽  
Yu Xia ◽  
Joseph B Balowski ◽  
jianhong ou ◽  
Lingyun Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Injury ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Heart Regeneration ◽  
Epicardial Cells ◽  
Transgenic Lines ◽  
Functional Features ◽  
Multiple Trees ◽  
Regulatory Controls

The epicardium is a mesothelial tissue layer that envelops the heart. Cardiac injury activates dynamic gene expression programs in epicardial tissue, which in the case of zebrafish enables subsequent regeneration through paracrine and vascularizing effects. To identify tissue regeneration enhancer elements (TREEs) that control injury-induced epicardial gene expression during heart regeneration, we profiled transcriptomes and chromatin accessibility in epicardial cells purified from regenerating zebrafish hearts. We identified hundreds of candidate TREEs, defined by increased chromatin accessibility of non-coding elements near genes with increased expression during regeneration. Several of these candidate TREEs were incorporated into stable transgenic lines, with 5 of 6 elements directing injury-induced epicardial expression but not ontogenetic epicardial expression in hearts of larval animals. Whereas two independent TREEs linked to the gene gnai3 showed similar functional features of gene regulation in transgenic lines, two independent ncam1a-linked TREEs directed distinct spatiotemporal domains of epicardial gene expression. Thus, multiple TREEs linked to a regeneration gene can possess either matching or complementary regulatory controls. Our study provides a new resource and principles for understanding the regulation of epicardial genetic programs during heart regeneration.

scholarly journals Vertebrate cardiac regeneration: evolutionary and developmental perspectives

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Stephen Cutie ◽  
Guo N. Huang
Keyword(s):  
Cardiac Injury ◽  
Adaptive Immune System ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Adaptive Immune ◽  
Selective Pressures ◽  
Trade Offs ◽  
Lower Vertebrates ◽  
Complex Adaptive ◽  
And Function

AbstractCardiac regeneration is an ancestral trait in vertebrates that is lost both as more recent vertebrate lineages evolved to adapt to new environments and selective pressures, and as members of certain species developmentally progress towards their adult forms. While higher vertebrates like humans and rodents resolve cardiac injury with permanent fibrosis and loss of cardiac output as adults, neonates of these same species can fully regenerate heart structure and function after injury – as can adult lower vertebrates like many teleost fish and urodele amphibians. Recent research has elucidated several broad factors hypothesized to contribute to this loss of cardiac regenerative potential both evolutionarily and developmentally: an oxygen-rich environment, vertebrate thermogenesis, a complex adaptive immune system, and cancer risk trade-offs. In this review, we discuss the evidence for these hypotheses as well as the cellular participators and molecular regulators by which they act to govern heart regeneration in vertebrates.

scholarly journals Myocardial NF-κB activation is essential for zebrafish heart regeneration

2015 ◽  
Vol 112 (43) ◽  
pp. 13255-13260 ◽  
Author(s):  
Ravi Karra ◽  
Anne K. Knecht ◽  
Kazu Kikuchi ◽  
Kenneth D. Poss
Keyword(s):  
Tissue Regeneration ◽  
Therapeutic Strategy ◽  
Cardiac Injury ◽  
Regulatory Sequences ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Developmental Program ◽  
Lower Vertebrates ◽  
Outstanding Question ◽  
Zebrafish Heart

Heart regeneration offers a novel therapeutic strategy for heart failure. Unlike mammals, lower vertebrates such as zebrafish mount a strong regenerative response following cardiac injury. Heart regeneration in zebrafish occurs by cardiomyocyte proliferation and reactivation of a cardiac developmental program, as evidenced by induction of gata4 regulatory sequences in regenerating cardiomyocytes. Although many of the cellular determinants of heart regeneration have been elucidated, how injury triggers a regenerative program through dedifferentiation and epicardial activation is a critical outstanding question. Here, we show that NF-κB signaling is induced in cardiomyocytes following injury. Myocardial inhibition of NF-κB activity blocks heart regeneration with pleiotropic effects, decreasing both cardiomyocyte proliferation and epicardial responses. Activation of gata4 regulatory sequences is also prevented by NF-κB signaling antagonism, suggesting an underlying defect in cardiomyocyte dedifferentiation. Our results implicate NF-κB signaling as a key node between cardiac injury and tissue regeneration.

scholarly journals Regulatory divergence in wound-responsive gene expression in domesticated and wild tomato

2017 ◽  
Author(s):  
Ming-Jung Liu ◽  
Koichi Sugimoto ◽  
Sahra Uygun ◽  
Nicholas Panchy ◽  
Michael S. Campbell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Transcriptional Response ◽  
Regulatory Elements ◽  
Expression Divergence ◽  
Solanum Pennellii ◽  
Responsive Gene ◽  
Mechanistic Basis ◽  
Species Specific ◽  
Regulatory Sites

ABSTRACTBackgroundThe evolution of cis- and trans-regulatory components of transcription is central to how stress response and tolerance differ across species. However, it remains largely unknown how divergence in TF binding specificity and cis-regulatory sites contribute to the divergence of stress-responsive gene expression between wild and domesticated species.ResultsUsing tomato as model, we analyzed the transcriptional profile of wound-responsive genes in wild Solanum pennellii and domesticated S. lycopersicum. We found that extensive expression divergence of wound-responsive genes is associated with speciation. To assess the degree of trans-regulatory divergence between these two species, 342 and 267 putative cis-regulatory elements (pCREs) in S. lycopersicum and S. pennellii, respectively, were identified that were predictive of wound-induced gene expression. We found that 35-66% of pCREs were conserved across species, suggesting that the remaining proportion (34-65%) of pCREs are species specific. This finding indicates a substantially higher degree of trans-regulatory divergence between these two plant species, which diverged ∼3-7 million years ago, compared to that observed in mouse and human, which diverged ∼100 million years ago. In addition, differences in pCRE sites were significantly associated with differences in wound-responsive gene expression between wild and domesticated tomato orthologs, suggesting the presence of substantial cis-regulatory divergence.ConclusionsOur study provides new insights into the mechanistic basis of how the transcriptional response to wounding is regulated and, importantly, the contribution of cis- and trans-regulatory components to variation in wound-responsive gene expression during species domestication.

Abstract 17364: G-protein Signaling Regulation of the Hippo Pathway in Neonatal Heart Regeneration

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Masahide Sakabe ◽  
Aishlin Hassan ◽  
Mei Xin
Keyword(s):  
G Protein ◽  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Adult Age ◽  
Rhoa Activity ◽  
Β Blocker

Introduction: The regeneration potential in the adult mammalian heart is very limited due to the cessation of cardiomyocyte proliferation shortly after birth. Recent studies have revealed that changes after birth such as metabolic state, oxygen level, cardiomyocyte structure and maturity, immune system and polyploidy are among the factors contributing to the loss of the regenerative potential in the heart. The mechanisms that regulate the cardiac regenerative window are not well understood. Here we report that G-protein mediated signaling regulates Hippo-YAP in neonatal cardiomyocyte proliferation and heart regeneration through Rho activity. Hypothesis: Gas encoded by the Gnas gene, a downstream effector of beta-adrenergic receptor (βAR) inhibits cardiomyocyte proliferation via regulation of YAP activity. Methods: We pharmacologically inhibited the G protein coupled receptor mediated β adrenergic signaling with a β-blocker (metoprolol) at early postnatal stages, and genetically by deleting Gnas in the heart with αMHC-Cre. We accessed the cardiomyocyte proliferation, heart regeneration in these mice and elucidated molecular mechanisms. Results: We found that β-blocker enhanced cardiomyocyte proliferation and promoted cardiac regeneration post cardiac injury with improved cardiac function. Consistent with β-blocker treated mice, mice lacking Gnas in cardiomyocytes exhibited enlarged hearts with an increase in cardiomyocyte proliferation. RNA-seq analysis revealed that these cardiomyocytes maintained an immature status even at young-adult age. The genes associated with mitochondrial oxidative metabolism, the major energy source for mature cardiomyocytes, were downregulated. Moreover, YAP activity was upregulated in both cases. We also found that loss of Gαs function caused upregulation of RhoA activity, and inhibitor of Rho signaling pathway suppressed the YAP activity in cardiomyocytes. Conclusions: Our study reveals that Gαs negatively regulate cardiomyocyte proliferation and provides mechanistic insight for β-blocker treatment as a strategy for inducing cardiac dedifferentiation and proliferation in injured heart.

scholarly journals The roles and activation of endocardial Notch signaling in heart regeneration

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Huicong Li ◽  
Cheng Chang ◽  
Xueyu Li ◽  
Ruilin Zhang
Keyword(s):  
Notch Signaling ◽  
Tissue Regeneration ◽  
Primary Cilia ◽  
Cardiac Injury ◽  
Notch Pathway ◽  
Heart Regeneration ◽  
Larval Zebrafish ◽  
Flow Change ◽  
Mechanosensitive Ion Channel ◽  
Stress Models

AbstractAs a highly conserved signaling pathway in metazoans, the Notch pathway plays important roles in embryonic development and tissue regeneration. Recently, cardiac injury and regeneration have become an increasingly popular topic for biomedical research, and Notch signaling has been shown to exert crucial functions during heart regeneration as well. In this review, we briefly summarize the molecular functions of the endocardial Notch pathway in several cardiac injury and stress models. Although there is an increase in appreciating the importance of endocardial Notch signaling in heart regeneration, the mechanism of its activation is not fully understood. This review highlights recent findings on the activation of the endocardial Notch pathway by hemodynamic blood flow change in larval zebrafish ventricle after partial ablation, a process involving primary cilia, mechanosensitive ion channel Trpv4 and mechanosensitive transcription factor Klf2.

Pre-existent adult sox10+ cardiomyocytes contribute to myocardial regeneration in the zebrafish

2019 ◽  
Author(s):  
Marcos Sande-Melón ◽  
Inês J. Marques ◽  
María Galardi-Castilla ◽  
Xavier Langa ◽  
María Pérez-López ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profile ◽  
Crucial Role ◽  
Cardiac Regeneration ◽  
Heart Regeneration ◽  
Adult Zebrafish ◽  
Genetic Ablation ◽  
Fibrotic Tissue ◽  
Distinct Gene Expression Profile ◽  
Zebrafish Heart

AbstractDuring heart regeneration in the zebrafish, fibrotic tissue is replaced by newly formed cardiomyocytes derived from pre-existing ones. It is unclear whether the heart is comprised of several cardiomyocyte populations bearing different capacity to replace lost myocardium. Here, using sox10 genetic fate mapping, we identified a subset of pre-existent cardiomyocytes in the adult zebrafish heart with a distinct gene expression profile that expanded massively after cryoinjury. Genetic ablation of sox10+ cardiomyocytes severely impaired cardiac regeneration revealing that they play a crucial role for heart regeneration.

scholarly journals Transcriptional Programs and Regeneration Enhancers Underlying Heart Regeneration

2018 ◽  
Vol 6 (1) ◽  
pp. 2
Author(s):  
Ian Begeman ◽  
Junsu Kang
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Heart Function ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Scar Tissue ◽  
Vital Role ◽  
Entire Body ◽  
Heart Regeneration ◽  
Altered Expression

The heart plays the vital role of propelling blood to the entire body, which is essential to life. While maintaining heart function is critical, adult mammalian hearts poorly regenerate damaged cardiac tissue upon injury and form scar tissue instead. Unlike adult mammals, adult zebrafish can regenerate injured hearts with no sign of scarring, making zebrafish an ideal model system with which to study the molecular mechanisms underlying heart regeneration. Investigation of heart regeneration in zebrafish together with mice has revealed multiple cardiac regeneration genes that are induced by injury to facilitate heart regeneration. Altered expression of these regeneration genes in adult mammals is one of the main causes of heart regeneration failure. Previous studies have focused on the roles of these regeneration genes, yet the regulatory mechanisms by which the expression of cardiac regeneration genes is precisely controlled are largely unknown. In this review, we will discuss the importance of differential gene expression for heart regeneration, the recent discovery of cardiac injury or regeneration enhancers, and their impact on heart regeneration.

scholarly journals Zebrafish cardiac regeneration—looking beyond cardiomyocytes to a complex microenvironment

2020 ◽  
Author(s):  
Rebecca Ryan ◽  
Bethany R. Moyse ◽  
Rebecca J. Richardson
Keyword(s):  
Cardiac Injury ◽  
Cell Communication ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Regenerative Process ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Underlying Mechanisms ◽  
Different Cell Types

Abstract The study of heart repair post-myocardial infarction has historically focused on the importance of cardiomyocyte proliferation as the major factor limiting adult mammalian heart regeneration. However, there is mounting evidence that a narrow focus on this one cell type discounts the importance of a complex cascade of cell–cell communication involving a whole host of different cell types. A major difficulty in the study of heart regeneration is the rarity of this process in adult animals, meaning a mammalian template for how this can be achieved is lacking. Here, we review the adult zebrafish as an ideal and unique model in which to study the underlying mechanisms and cell types required to attain complete heart regeneration following cardiac injury. We provide an introduction to the role of the cardiac microenvironment in the complex regenerative process and discuss some of the key advances using this in vivo vertebrate model that have recently increased our understanding of the vital roles of multiple different cell types. Due to the sheer number of exciting studies describing new and unexpected roles for inflammatory cell populations in cardiac regeneration, this review will pay particular attention to these important microenvironment participants.

Abstract 12781: NF-κB Activity is Required for Heart Regeneration

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ravi Karra ◽  
Anne Knecht ◽  
Kenneth D Poss
Keyword(s):  
Cardiac Injury ◽  
Transcriptional Response ◽  
Transgenic Zebrafish ◽  
Regulatory Sequences ◽  
Low Grade ◽  
Heart Regeneration ◽  
Rna Seq ◽  
Early Transcriptional Response ◽  
Light Chain Enhancer ◽  
Zebrafish Heart

Objectives: In contrast to humans, zebrafish recover from cardiac injury through a robust regenerative response. Recent work suggests that the mammalian heart is able to undergo low-grade cardiomyocyte turnover in response to injury. However, this level of turnover in not sufficient for cardiac recovery. A better understanding of the mechanisms that contribute to zebrafish heart regeneration can instruct approaches to achieve therapeutic heart regeneration in humans. Methods and Results: We performed expression profiling of regenerating zebrafish hearts by RNA-Seq to identify factors that modify heart regeneration. Expression levels for members of the NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) pathway were significantly enriched in regenerating hearts. Using a transgenic reporter strain for NF-κB activity, we found NF-κB to be induced in cardiomyocytes following injury. Moreover, NF-κB activity overlaps with the activation of gata4 regulatory sequences that are induced in regenerating cardiomyocytes. We subsequently developed a transgenic zebrafish strain to conditionally inhibit NF-κB signaling in cardiomyocytes by expression of mutant IκBα. Zebrafish hearts with loss of NF-κB activity scar following injury, indicative of impaired regeneration. Conclusions: NF-κB mediates an early transcriptional response to injury in cardiomyocytes that is required for heart regeneration.

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