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Regenerating zebrafish fin epigenome is characterized by stable lineage-specific DNA methylation and dynamic chromatin accessibility (RNA-seq)

ABSTRACT: Background: Zebrafish can faithfully regenerate injured fins through the formation of a blastema, a mass of proliferative cells that can grow and develop into the lost body part. After amputation, various cell types contribute to blastema formation, where each cell type retains fate restriction and exclusively contributes to regeneration of its own lineage. Epigenetic changes that are associated with lineage restriction during regeneration remain underexplored. Results: We produce epigenome maps, including DNA methylation and chromatin accessibility, as well as transcriptomes, of osteoblasts and other cells in uninjured and regenerating fins. This effort reveals regeneration as a process of highly dynamic and orchestrated transcriptomic and chromatin accessibility changes, coupled with stably maintained lineage-specific DNA methylation. The epigenetic signatures also reveal many novel regeneration-specific enhancers, which are experimentally validated. Regulatory networks important for regeneration are constructed through integrative analysis of the epigenome map, and a knockout of a predicted upstream regulator disrupts normal regeneration, validating our prediction. Conclusion: Our study shows that lineage-specific DNA methylation signatures are stably maintained during regeneration, and regeneration enhancers are preset as hypomethylated before injury. In contrast, chromatin accessibility is dynamically changed during regeneration. Many enhancers driving regeneration gene expression as well as upstream regulators of regeneration are identified and validated through integrative epigenome analysis.

ORGANISM(S): Danio rerio

PROVIDER: GSE126701 | GEO | 2020/01/20

REPOSITORIES: GEO

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Regenerating zebrafish fin epigenome is characterized by stable lineage-specific DNA methylation and dynamic chromatin accessibility (WGBS)

Project description:Background: Zebrafish can faithfully regenerate injured fins through the formation of a blastema, a mass of proliferative cells that can grow and develop into the lost body part. After amputation, various cell types contribute to blastema formation, where each cell type retains fate restriction and exclusively contributes to regeneration of its own lineage. Epigenetic changes that are associated with lineage restriction during regeneration remain underexplored. Results: We produce epigenome maps, including DNA methylation and chromatin accessibility, as well as transcriptomes, of osteoblasts and other cells in uninjured and regenerating fins. This effort reveals regeneration as a process of highly dynamic and orchestrated transcriptomic and chromatin accessibility changes, coupled with stably maintained lineage-specific DNA methylation. The epigenetic signatures also reveal many novel regeneration-specific enhancers, which are experimentally validated. Regulatory networks important for regeneration are constructed through integrative analysis of the epigenome map, and a knockout of a predicted upstream regulator disrupts normal regeneration, validating our prediction. Conclusion: Our study shows that lineage-specific DNA methylation signatures are stably maintained during regeneration, and regeneration enhancers are preset as hypomethylated before injury. In contrast, chromatin accessibility is dynamically changed during regeneration. Many enhancers driving regeneration gene expression as well as upstream regulators of regeneration are identified and validated through integrative epigenome analysis.

2020-01-20 | GSE126702 | GEO

Regenerating zebrafish fin epigenome is characterized by stable lineage-specific DNA methylation and dynamic chromatin accessibility (ATAC-seq)

2020-01-20 | GSE126700 | GEO

Calcineurin Controls Proximodistal Blastema Polarity in Zebrafish Fin Regeneration

Project description:Planarian flatworms regenerate their heads and tails from anterior or posterior wounds and this blastema regeneration polarity is controlled by Wnt/β-catenin signaling. It is well known that a regeneration blastema of appendages of vertebrates such as fish and amphibians grows distally. However, it remains unclear whether a regeneration blastema in vertebrate appendages can grow proximally. Here, we show that a regeneration blastema in zebrafish fins can grow proximally along the proximodistal axis by calcineurin inhibition. We used fin excavation in adult zebrafish to observe the unidirectional regeneration, from the anterior cut edge (ACE) to the posterior cut edge (PCE) of the cavity and this unidirectional regeneration polarity occurs as the PCE fails to build blastemas. Furthermore, we found that calcineurin activities in the ACE were greater than in the PCE. Calcineurin inhibition induced the PCE blastemas, and calcineurin hyperactivation suppressed fin regeneration. Collectively, these findings identify calcineurin as a molecular switch to specify the PCE blastema of the proximodistal axis and regeneration polarity in zebrafish fin.

2020-10-20 | GSE159560 | GEO

Single cell RNA sequencing of adult regenerating mouse digit tips

Project description:Innate regeneration following digit tip amputation is one of the few examples of epimorphic regeneration in mammals. Digit tip regeneration is mediated by the blastema, the same structure invoked during limb regeneration in some lower vertebrates. By genetic lineage analyses in mice, the digit tip blastema has been defined as a population of heterogeneous, lineage restructed progenitor cells. These previous studies, however, do not comprehensively evaluate blastema heterogeneity or address lineage restruction of closely related cell types. Here we report single cell RNA sequencing of over 38,000 cells from mouse digit tip blastemas and unamputated control digit tips and generate an atlas of the cell types participating in digit tip regeneration.

2020-02-24 | GSE143888 | GEO

Acquisition of a unique mesenchymal precursor-like blastema state underlies successful adult mammalian digit tip regeneration

Project description:Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra-expressing mesenchymal cells in uninjured digits establish the regenerative blastema and are essential for regeneration. Single cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb/digit Pdgfra-positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema markers and contribute to bone regeneration. Moreover, lineage tracing with single cell profiling indicates that endogenous osteoblasts/osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a unique blastema state that allows cells from tissues like bone to contribute to regeneration of other mesenchymal tissues such as the dermis.

2019-11-15 | GSE135985 | GEO

Positional information modulates transient regeneration-activated cell states during vertebrate appendage regeneration.

Project description:Injury is a common occurrence in the life of most if not all organisms. Because injury and the extent of damage inflicted are not predictable events, pre-existing tissues must somehow determine how much tissue needs to be restored. It has been known for over a century that amputation position along a proximal-distal (P/D) axis determines the regeneration speed of amputated limbs in regeneration-competent animals1. Yet, it is not clear how an injured limb conveys positional information during regeneration to faithfully restore pre-existing morphologies and functions. Here, we profiled millimetric caudal fins regenerating proximal and distal amputations in the African killifish (Nothobranchius furzeri). We report position-specific, differential modulation of the spatial distribution, duration, and magnitude of proliferation, and the possibility to predict blastema sizes. Regenerating fins profiled by single cell RNA sequencing identified a Transient Regeneration-Activated Cell State (TRACS) enriched in extracellular matrix (ECM) components and modifiers that is proportionally amplified to match a given amputation position. We located this transient cell state to the basal epidermis by gene expression and confocal microscopy, and propose a role for these cells in transducing positional information to the regeneration blastema. Understanding the temporal deployment of regenerative cell states may hold the key to set up a successful regeneration event in organisms with limited regenerative abilities such as humans.

2024-04-01 | GSE260629 | GEO

Spatial transcriptomics reveals increased energetic requirements underpinning age-dependent declines in digit regeneration rescued through administration of OAA

Project description:De novo limb regeneration after amputation is restricted in mammals to the distal digit tip. Central to this regenerative process is the blastema, a heterogeneous population of lineage-restricted, dedifferentiated cells that ultimately orchestrates the regeneration of the amputated bone and surrounding soft tissue. To investigate skeletal regeneration, we made use of spatial transcriptomics to characterize the transcriptional profile specifically within the blastema. Using this technique, we generated a gene signature with high specificity for the blastema in both our spatial data, as well as other previously published single-cell RNA-sequencing transcriptomic studies. To elucidate potential mechanisms distinguishing regenerative from non-regenerative healing, we applied spatial transcriptomics to an aging model. Consistent with other forms of repair, our digit amputation mouse model showed a significant impairment in regeneration in aged mice. Contrasting young and aged mice, spatial analysis revealed a metabolic shift in aged blastema associated with an increased bioenergetic requirement. This enhanced metabolic turnover was associated with increased hypoxia and angiogenic signaling, leading to excessive vascularization and altered regenerated bone architecture in aged mice. Restoration of this metabolic deficiency using the metabolite oxaloacetate enhanced in vivo bone regeneration. Thus, targeting cell metabolism may be a promising strategy to mitigate aging-induced declines in tissue regeneration.

2022-06-01 | GSE180682 | GEO

Nail-associated mesenchymal cells contribute to and are essential for dorsal digit tip regeneration

Project description:Here, we have asked why the nail base is essential for mammalian digit tip regeneration, focusing on the inductive nail mesenchyme. We identify a transcriptional signature for these cells that includes Lmx1b, and show that the Lmx1b-expressing nail mesenchyme is essential for blastema formation. We use a combination of Lmx1bCreERT2-based lineage tracing and single cell transcriptional analyses to show that the nail mesenchyme contributes cells for two pro-regenerative mechanisms. One group of cells maintains their identity and regenerates the new nail mesenchyme. A second group contributes specifically to the dorsal blastema, loses their nail mesenchyme phenotype, acquires a blastema transcriptional state that is highly similar to blastema cells of other origins and ultimately contributes to regeneration of the dorsal but not ventral dermis and bone. Thus, the regenerative necessity for an intact nail base is explained, at least part by a requirement for the inductive nail mesenchyme.

2022-11-16 | GSE217600 | GEO

Active DNA demethylation during the vertebrate phylotypic period

Project description:The vertebrate body plan and organs are shaped during a highly conserved embryonic phase called the phylotypic stage, however the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of thousands of enhancers during the phylotypic period in zebrafish, Xenopus and mouse. These dynamic enhancers are linked to essential developmental genes that display coordinated transcriptional and epigenomic changes in the diverse vertebrates during embryogenesis. Phylotypic stage-specific binding of Tet proteins to (hydroxy)methylated DNA, and enrichment of hydroxymethylcytosine on these enhancers, implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1/2/3 in zebrafish caused reduced chromatin accessibility and increased methylation levels specifically on these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study reveals a novel regulatory module associated with the most conserved phase of vertebrate embryogenesis and uncovers an ancient developmental role for the Tet dioxygenases.

2016-01-27 | PXD001164 | Pride

HiCAR analysis of zebrafish fin regeneration identifies cis-regulatory chromatin reorganization in response to injury

Project description:HiCAR (Hi-C on accessible regulatory DNA), which is a genome-wide profiling of chromatin accessibility and open chromatin anchored cis-regulatory element (cRE) interactions, identified 28690 calling loops from zebrafish caudal fins at three different time points (0, 1 and 4 day(s) post amputation (dpa)) including 5022 regeneration-responsive loops (17.5%).

2023-12-22 | GSE231771 | GEO

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