Nuclear S-nitrosylation impacts tissue regeneration in zebrafish

Matrone, Gianfranco; Jung, Sung Yun; Choi, Jong Min; Jain, Antrix; Leung, Hon‐Chiu Eastwood; Rajapakshe, Kimal I.; Coarfa, Cristian; Rodor, Julie; Denvir, Martin A.; Baker, Andrew H.; Cooke, John P.

doi:10.1038/s41467-021-26621-0

Cited by 12 publications

(3 citation statements)

References 43 publications

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“…And while both ROS and RNS have been shown to play roles during cell proliferation and new tissue growth, the mechanisms of RNS signaling during regeneration are much less well understood [85,86]. Although a recent study has demonstrated a role for NO during zebrafish fin regeneration [87], the role of RNS in the regenerative process is still largely uncharacterized and its role during planarian regeneration is currently unknown. Given the potential, based on the radical pair mechanism, for WMF interactions with RNS signaling during tissue growth, this is a promising area for further studies.…”

Section: Discussionmentioning

confidence: 99%

Weak magnetic fields modulate superoxide to control planarian regeneration

2023

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Reactive oxygen species (ROS) signaling regulates cell behaviors and tissue growth in development, regeneration, and cancer. Commonly, ROS are modulated pharmacologically, which while effective comes with potential complications such as off-target effects and lack of drug tolerance. Thus, additional non-invasive therapeutic methods are necessary. Recent advances have highlighted the use of weak magnetic fields (WMFs, <1 mT) as one promising approach. We previously showed that 200 μT WMFs inhibit ROS formation and block planarian regeneration. However, WMF research in different model systems at various field strengths have produced a range of results that do not fit common dose response curves, making it unclear if WMF effects are predictable. Here, we test hypotheses based on spin state theory and the radical pair mechanism, which outlines how magnetic fields can alter the formation of radical pairs by changing electron spin states. This mechanism suggests that across a broad range of field strengths (0–900 μT) some WMF exposures should be able to inhibit while others promote ROS formation in a binary fashion. Our data reveal that WMFs can be used for directed manipulation of stem cell proliferation, differentiation, and tissue growth in predictable ways for both loss and gain of function during regenerative growth. Furthermore, we examine two of the most common ROS signaling effectors, hydrogen peroxide and superoxide, to begin the identification and elucidation of the specific molecular targets by which WMFs affect tissue growth. Together, our data reveal that the cellular effects of WMF exposure are highly dependent on ROS, and we identify superoxide as a specific ROS being modulated. Altogether, these data highlight the possibilities of using WMF exposures to control ROS signaling in vivo and represent an exciting new area of research.

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Section: Discussionmentioning

confidence: 99%

Weak magnetic fields modulate superoxide to control planarian regeneration

2023

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“…In similar experimental settings, we next detected the transcript level expression of NO-responsive genes in EC using qPCR experiment. Based on previously reported data sets, we choose to detect the transcript level of NO responsive genes; VEGFa, TBX20, MMP2, FGF2, KDR, TIE2, TEK, and Angiopoietin-2 26 . Through this analysis, we detected significant increase in expression of VEGFa, TBX20, MMP2, FGF2, and Angiopoietin-2 upon NO exposure (Fig.…”

Section: Resultsmentioning

confidence: 99%

S-nitrosylation of EZH2 at C329 and C700 interplay with PRC2 complex assembly, methyltransferase activity, and EZH2 stability to regulate endothelial functions

Sakhuja,

Katakia,

Tripathi

et al. 2024

Preprint

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Nitric oxide (NO), a versatile bio-active molecule modulates cellular function through diverse mechanisms including S-nitrosylation of proteins. However, the role of this post-translational modification in regulating epigenetic pathways was very limitedly explored. Herein, we report that NO causes S-nitrosylation of selected cysteine residues of EZH2 in endothelial cells (EC) resulting in SUZ12 dissociation from EZH2 bound PRC2 complex, reduced methyltransferase activity, and diminished nuclear localization eventually hampering its stability. We detected a significant reduction in H3K27me3 upon exposure to NO as contributed by the early dissociation of SUZ12 from the PRC2 complex. Longer exposure to NO donors caused EZH2 cytosolic translocation, its ubiquitination, and further degradation primarily through the autophagosome-lysosome pathway. Through in silico S-nitrosylation prediction analysis and site-directed mutagenesis assay, we identified three cysteine residues namely at locations 260, 329, and 700 in EZH2 and further determined that S-nitrosylation of cysteine 329 induced EZH2 instability while S-nitrosylation of cysteine 700 abrogated EZH2 catalytic activity. A double mutant of EZH2 containing mutations at Cysteine 329 and 700 remained undeterred to NO exposure. Furthermore, reinforcing H3K27me3 in NO exposed EC through the use of an inhibitor of H3K27me3 demethylase, we confirmed a significant contribution of the EZH2-H3K27me3 axis in defining NO-mediated regulation of endothelial gene expression and migration. Molecular dynamics simulation study revealed SUZ12 inability in efficiently binding to the SAL domain of EZH2 upon S-nitrosylation of C329 and C700. Taken together, our study for the first-time reports that S-nitrosylation dependent regulation of EZH2 and its associated PRC2 complex influences endothelial homeostasis.

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“…They also demonstrated that NO signaling results in increased protein S-nitrosylation. This later process may however be beneficial as Matrone et al demonstrated that inhibition of the NO synthase iNOS results in reduced nuclear S-nitrosylation and impaired regeneration following tail fin amputation [306].…”

Section: Induction Of Inflammationmentioning

confidence: 99%

Molecular Actors of Inflammation and Their Signaling Pathways: Mechanistic Insights from Zebrafish

Leiba

Özbilgiç

Hernández

et al. 2023

Biology

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Inflammation is a hallmark of the physiological response to aggressions. It is orchestrated by a plethora of molecules that detect the danger, signal intracellularly, and activate immune mechanisms to fight the threat. Understanding these processes at a level that allows to modulate their fate in a pathological context strongly relies on in vivo studies, as these can capture the complexity of the whole process and integrate the intricate interplay between the cellular and molecular actors of inflammation. Over the years, zebrafish has proven to be a well-recognized model to study immune responses linked to human physiopathology. We here provide a systematic review of the molecular effectors of inflammation known in this vertebrate and recapitulate their modes of action, as inferred from sterile or infection-based inflammatory models. We present a comprehensive analysis of their sequence, expression, and tissue distribution and summarize the tools that have been developed to study their function. We further highlight how these tools helped gain insights into the mechanisms of immune cell activation, induction, or resolution of inflammation, by uncovering downstream receptors and signaling pathways. These progresses pave the way for more refined models of inflammation, mimicking human diseases and enabling drug development using zebrafish models.

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Nuclear S-nitrosylation impacts tissue regeneration in zebrafish

Cited by 12 publications

References 43 publications

Weak magnetic fields modulate superoxide to control planarian regeneration

Weak magnetic fields modulate superoxide to control planarian regeneration

S-nitrosylation of EZH2 at C329 and C700 interplay with PRC2 complex assembly, methyltransferase activity, and EZH2 stability to regulate endothelial functions

Molecular Actors of Inflammation and Their Signaling Pathways: Mechanistic Insights from Zebrafish

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