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Project description:ObjectivesCutaneous wound healing is one of the major medical problems worldwide. Epigenetic modifiers have been identified as important players in skin development, homeostasis and wound repair. SET domain-containing 2 (SETD2) is the only known histone H3K36 tri-methylase; however, its role in skin wound healing remains unclear.Materials and methodsTo elucidate the biological role of SETD2 in wound healing, conditional gene targeting was used to generate epidermis-specific Setd2-deficient mice. Wound-healing experiments were performed on the backs of mice, and injured skin tissues were collected and analysed by haematoxylin and eosin (H&E) and immunohistochemical staining. In vitro, CCK8 and scratch wound-healing assays were performed on Setd2-knockdown and Setd2-overexpression human immortalized keratinocyte cell line (HaCaT). In addition, RNA-seq and H3K36me3 ChIP-seq analyses were performed to identify the dysregulated genes modulated by SETD2. Finally, the results were validated in functional rescue experiments using AKT and mTOR inhibitors (MK2206 and rapamycin).ResultsEpidermis-specific Setd2-deficient mice were successfully established, and SETD2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing by promoting keratinocyte proliferation and migration. Furthermore, the loss of SETD2 enhanced the scratch closure and proliferation of keratinocytes in vitro. Mechanistically, the deletion of Setd2 resulted in the activation of AKT/mTOR signalling pathway, while the pharmacological inhibition of AKT and mTOR with MK2206 and rapamycin, respectively, delayed wound closure.ConclusionsOur results showed that SETD2 loss promoted cutaneous wound healing via the activation of AKT/mTOR signalling.
| S-EPMC8168411 | biostudies-literature
Project description:Skin wound healing is one of the major prevalent medical problems in the worldwide. Wound healing involves multi-process synergy and re-epithelialization is an essential part of wound healing. Histone H3K36 tri-methylase Setd2 has been extensively studied in different biological processes and diseases. However, the function of Setd2 in the wound healing remains unclear. To elucidate the biological role of Setd2 in the skin wound healing, conditional gene targeting was employed to establish epidermis-specific Setd2-deficient mice. We found that Setd2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing by promoting keratinocytes proliferation and migration. Furthermore, we demonstrated that loss of Setd2 activated the AKT/mTOR pathway, and pharmacological inhibitions of AKT and mTOR with MK2206 and rapamycin delayed wound closure, respectively. In conclusion, our results reveal the essential role of Setd2 in skin wound healing that is Setd2 loss promotes cutaneous wound healing via activation of AKT/mTOR signaling.
2020-12-25 | GSE163860 | GEO
Project description:Skin wound healing is one of the major prevalent medical problems in the worldwide. Wound healing involves multi-process synergy and re-epithelialization is an essential part of wound healing. Histone H3K36 tri-methylase Setd2 has been extensively studied in different biological processes and diseases. However, the function of Setd2 in the wound healing remains unclear. To elucidate the biological role of Setd2 in the skin wound healing, conditional gene targeting was employed to establish epidermis-specific Setd2-deficient mice. We found that Setd2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing by promoting keratinocytes proliferation and migration. Furthermore, we demonstrated that loss of Setd2 activated the AKT/mTOR pathway, and pharmacological inhibitions of AKT and mTOR with MK2206 and rapamycin delayed wound closure, respectively. In conclusion, our results reveal the essential role of Setd2 in skin wound healing that is Setd2 loss promotes cutaneous wound healing via activation of AKT/mTOR signaling.
2020-12-25 | GSE163858 | GEO
Project description:Setd2 Epidermal Deficiency Promotes Cutaneous Wound Healing via Activation of AKT/mTOR Signaling
| PRJNA687765 | ENA
Project description:Setd2 Epidermal Deficiency Promotes Cutaneous Wound Healing via Activation of AKT/mTOR Signaling (ChIP-Seq)
| PRJNA687766 | ENA
Project description:Setd2 Epidermal Deficiency Promotes Cutaneous Wound Healing via Activation of AKT/mTOR Signaling (RNA-Seq)
| PRJNA687767 | ENA
Project description:Oral mucosa contains a unique transcriptional network that primes oral wounds for rapid resolution in humans. Our previous work identified genes that were consistently upregulated in the oral mucosa and demonstrated that induction of one of the identified genes, transcription factor SOX2, promoted cutaneous wound healing in mice. In this study, we investigated the molecular and cellular mechanisms by which SOX2 accelerates wound healing in skin. RNA-sequencing analysis showed that SOX2 induced a proliferative and wound-activated phenotype in skin keratinocytes prior to wounding. During wound healing, SOX2 induced proliferation of epithelial and connective tissue cells and promoted angiogenesis. Chromatin immunoprecipitation assay revealed that SOX2 directly regulates expression of EGFR ligands, resulting in activation of EGFR. In vitro, skin keratinocytes overexpressing SOX2 promoted cell migration via the EGFR/MEK/ERK pathway. We conclude that induction of SOX2 in skin keratinocytes accelerates cutaneous wound healing by promoting keratinocyte migration and proliferation, and enhancement of angiogenesis via upregulation of EGFR ligands and activation of EGFR/MEK/ERK pathway. Through the identification of putative cutaneous SOX2 targets, such as HBEGF, this study opens venues to determine clinical targets for treatment of skin wounds.
| S-EPMC6650375 | biostudies-literature
Project description:We perfomed RNA-seq and wound healing analysis to identify the mechanism how SOX2 promote wound healing. We showed that induction of SOX2 in skin keratinocytes accelerates cutaneous wound healing by promoting keratinocyte migration and proliferation, and enhancement of angiogenesis via the upregulation of EGFR ligands.
2019-09-02 | GSE118859 | GEO
Project description:P311 was identified to markedly promote cutaneous wound healing by our group. Angiogenesis plays a key role in wound healing. In this study, we sought to define the role of P311 in skin wound angiogenesis. It was noted that P311 was expressed in endothelial cells in the dermis of murine and human skin wounds. The expression of P311 was confirmed in cultured murine dermal microvascular endothelial cells (mDMECs). Moreover, it was found that knockout of P311 could attenuate the formation of tubes and motility of mDMECs significantly in vitro. In the subcutaneous Matrigel implant model, the angiogenesis was reduced significantly in P311 knockout mice. In addition, wound healing was delayed in P311 knockout mice compared with that in the wild type. Granulation tissue formation during the defective wound healing showed thinner and blood vessel numbers in wound areas in P311 knockout mice were decreased significantly. A reduction in VEGF and TGF?1 was also found in P311 KO mice wounds, which implied that P311 may modulate the exprssion of VEGF and TGF?1 in wound healing. Together, our findings suggest that P311 plays an important role in angiogenesis in wound healing.
| S-EPMC5723677 | biostudies-literature
Project description:Wound healing consists of a complex, dynamic and overlapping process involving inflammation, proliferation and tissue remodeling. A better understanding of wound healing process at the molecular level is needed for the development of novel therapeutic strategies. Receptor-interacting protein kinase 3 (RIPK3) controls programmed necrosis in response to TNF-α during inflammation and has been shown to be highly induced during cutaneous wound repair. However, its role in wound healing remains to be demonstrated. To study this, we created dorsal cutaneous wounds on male wild-type (WT) and RIPK3-deficient (Ripk3-/-) mice. Wound area was measured daily until day 14 post-wound and skin tissues were collected from wound sites at various days for analysis. The wound healing rate in Ripk3-/- mice was slower than the WT mice over the 14-day course; especially, at day 7, the wound size in Ripk3-/- mice was 53% larger than that of WT mice. H&E and Masson-Trichrome staining analysis showed impaired quality of wound closure in Ripk3-/- wounds with delayed re-epithelialization and angiogenesis and defected granulation tissue formation and collagen deposition compared to WT. The neutrophil infiltration pattern was altered in Ripk3-/- wounds with less neutrophils at day 1 and more neutrophils at day 3. This altered pattern was also reflected in the differential expression of IL-6, KC, IL-1β and TNF-α between WT and Ripk3-/- wounds. MMP-9 protein expression was decreased with increased Timp-1 mRNA in the Ripk3-/- wounds compared to WT. The microvascular density along with the intensity and timing of induction of proangiogenic growth factors VEGF and TGF-β1 were also decreased or delayed in the Ripk3-/- wounds. Furthermore, mouse embryonic fibroblasts (MEFs) from Ripk3-/- mice migrated less towards chemoattractants TGF-β1 and PDGF than MEFs from WT mice. These results clearly demonstrate that RIPK3 is an essential molecule to maintain the temporal manner of the normal progression of wound closure.
| S-EPMC4599740 | biostudies-literature