The Methylome and Transcriptome of Fetal Skin: Implications for Scarless Healing

Podolak-Popinigis, Justyna; Ronowicz, Anna; Dmochowska, Monika; Jakubiak, Agnieszka; Sachadyn, Paweł

doi:10.2217/epi-2016-0068

Cited by 14 publications

(11 citation statements)

References 59 publications

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“…Regeneration potential is known to decrease with organism development. The spectacular regenerative abilities in the embryonic and neonatal stages, such as scarless skin wound healing in mammalian foetuses [1], cardiac repair in neonatal mice [2] and spinal cord regeneration following complete transection in opossum pups [3], are lost in adulthood. Development is driven by epigenetic reprogramming, while epigenetic reprogramming is critical for cells to acquire pluripotency [4].…”

Section: Introductionmentioning

confidence: 99%

“…Development is driven by epigenetic reprogramming, while epigenetic reprogramming is critical for cells to acquire pluripotency [4]. Several observations in animal models indicate the significance of the epigenetic status for regeneration capability [1,[5], [6], [7]].…”

Section: Introductionmentioning

confidence: 99%

“…As the decline in regenerative capacity with development is likely to be linked to epigenetic repression [1,[5], [6], [7],28,29], the question arises as to whether epigenetic inhibitors can restore this lost ability. Epigenetic derepression alone may be insufficient to activate silenced genes without positive induction.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic inhibitor zebularine activates ear pinna wound closure in the mouse

et al. 2019

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Background Most studies on regenerative medicine focus on cell-based therapies and transplantations. Small-molecule therapeutics, though proved effective in different medical conditions, have not been extensively investigated in regenerative research. It is known that healing potential decreases with development and developmental changes are driven by epigenetic mechanisms, which suggests epigenetic repression of regenerative capacity. Methods We applied zebularine, a nucleoside inhibitor of DNA methyltransferases, to stimulate the regenerative response in a model of ear pinna injury in mice. Findings We observed the regeneration of complex tissue that was manifested as improved ear hole repair in mice that received intraperitoneal injections of zebularine. Six weeks after injury, the mean hole area decreased by 83.2 ± 9.4% in zebularine-treated and by 43.6 ± 15.4% in control mice (p < 10 −30 ). Combined delivery of zebularine and retinoic acid potentiated and accelerated this effect, resulting in complete ear hole closure within three weeks after injury. We found a decrease in DNA methylation and transcriptional activation of neurodevelopmental and pluripotency genes in the regenerating tissues. Interpretation This study is the first to demonstrate an effective induction of complex tissue regeneration in adult mammals using zebularine. We showed that the synergistic action of an epigenetic drug (zebularine) and a transcriptional activator (retinoic acid) could be effectively utilized to induce the regenerative response, thus delineating a novel pharmacological strategy for regeneration. The strategy was effective in the model of ear pinna regeneration in mice, but zebularine acts on different cell types, therefore, a similar approach can be tested in other tissues and organs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic inhibitor zebularine activates ear pinna wound closure in the mouse

et al. 2019

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“…The gold standard of wound healing is a barely perceptible pale scar. During the first and second trimester of gestation, scarless healing is possible and there is increasing evidence that this ability depends on epigenetic regulation, particularly methylation 110 …”

Section: Micrornasmentioning

confidence: 99%

A review of epigenetic regulation in wound healing: Implications for the future of wound care

Lewis

Stevenson

Fear

et al. 2020

Wound Repair Regeneration

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Epigenetic regulatory mechanisms are essential for maintaining skin homeostasis and aid in the processes of wound healing. The nucleus co‐ordinates gene expression using epigenetic regulatory mechanisms based on distinct chromatin structural states and their remodeling. These include DNA methylation and hydroxymethylation, post‐translational histone modifications, ATP‐dependent chromatin remodeling and higher‐order chromatin structure and 3D genome organization. Epigenetic pathways play a key role in co‐ordinating the behavior and activity of the multitude of cell types seen during skin repair, and research is now focusing on how wound healing can be modulated by altering the activity of certain reparative genes. Herein, we aim to highlight recent advances in understanding epigenetic regulatory mechanisms, with particular reference to those involved in keratinocyte and fibroblast biology. We also propose future directions for exploration of epigenetic mechanisms, and their potential clinical applications in acute wound care.

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“…Though scar formation is a typical outcome of wound healing in mammals, unusual wound repair phenomena are observed in foetal and neonatal periods. Scarless skin wound healing occurs in mammals in the foetal period up to the beginning of the 3rd trimester [ 6 – 8 ]. On the other hand, burn wounds result in scarring even in the foetus [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic responses to wounding: meta-analysis of gene expression microarray data

et al. 2017

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BackgroundA vast amount of microarray data on transcriptomic response to injury has been collected so far. We designed the analysis in order to identify the genes displaying significant changes in expression after wounding in different organisms and tissues. This meta-analysis is the first study to compare gene expression profiles in response to wounding in as different tissues as heart, liver, skin, bones, and spinal cord, and species, including rat, mouse and human.ResultsWe collected available microarray transcriptomic profiles obtained from different tissue injury experiments and selected the genes showing a minimum twofold change in expression in response to wounding in prevailing number of experiments for each of five wound healing stages we distinguished: haemostasis & early inflammation, inflammation, early repair, late repair and remodelling. During the initial phases after wounding, haemostasis & early inflammation and inflammation, the transcriptomic responses showed little consistency between different tissues and experiments. For the later phases, wound repair and remodelling, we identified a number of genes displaying similar transcriptional responses in all examined tissues. As revealed by ontological analyses, activation of certain pathways was rather specific for selected phases of wound healing, such as e.g. responses to vitamin D pronounced during inflammation. Conversely, we observed induction of genes encoding inflammatory agents and extracellular matrix proteins in all wound healing phases. Further, we selected several genes differentially upregulated throughout different stages of wound response, including established factors of wound healing in addition to those previously unreported in this context such as PTPRC and AQP4.ConclusionsWe found that transcriptomic responses to wounding showed similar traits in a diverse selection of tissues including skin, muscles, internal organs and nervous system. Notably, we distinguished transcriptional induction of inflammatory genes not only in the initial response to wounding, but also later, during wound repair and tissue remodelling.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4202-8) contains supplementary material, which is available to authorized users.

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The Methylome and Transcriptome of Fetal Skin: Implications for Scarless Healing

Cited by 14 publications

References 59 publications

Epigenetic inhibitor zebularine activates ear pinna wound closure in the mouse

Epigenetic inhibitor zebularine activates ear pinna wound closure in the mouse

A review of epigenetic regulation in wound healing: Implications for the future of wound care

Transcriptomic responses to wounding: meta-analysis of gene expression microarray data

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