BCL11A deficiency protects epidermis from UVB-induced damage through promotion of autophagy
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ABSTRACT:
PROVIDER: PRJNA1308978 | ENA |
REPOSITORIES: ENA
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Project description:As a major environmental pathogenic factor for various skin diseases, UVB radiation leads to oxidative stress and biomacromolecule damage. Autophagy is a highly conserved catabolic process and serves as one of the main mechanisms to maintain cellular homeostasis. Here, by CRISPR/Cas9-mediated gene deletion, we demonstrate that the essential transcriptional repressor BCL11A is involved in autophagy regulation and participates in the UVB-induced stress response. BCL11A deficiency increases autophagosome formation and enhances the intensity of autophagy flux with or without UVB stress. Mechanistically, ACSS3, rather than autophagy-related genes, is identified as the direct target gene and transcriptionally repressed by BCL11A. Further, BCL11A deficiency reduces DNA damage and ROS to promote survival and inhibit apoptosis under UVB irradiation, which is blocked by pharmacological inhibition of autophagy or BCL11A overexpression. Collectively, BCL11A deficiency promotes autophagy activation to clear ROS and DNA damage, thereby protecting epidermal cells from UVB-induced death.
2025-08-27 | GSE306030 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE38622: Bmal1 controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis [telogen]. GSE38623: Bmal1 controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis [Anagen] GSE38624: Bmal1 controls circadian cell proliferation and susceptibility to UVB-induced DNA damage in the epidermis [Bmal1 KO] Refer to individual Series
2012-08-01 | E-GEOD-38625 | biostudies-arrayexpress
Project description:Total RNA was extracted from the basal epidermis derived from UVB-irradiated P2.5 normal (Mc1r+/Mc1r+; Kit+/Kit+), Mc1r-mutant (Mc1re/Mc1re) and Kit-mutant (Kit/W-v/Kit/W-v) mice. Biological replicates (cy5) were labelled and co-hybridized with a reference RNA sample (cy3) to a 35K mouse cDNA microarray. A reference experiement design type is where all samples are compared to a common reference. Keywords: reference_design
2007-07-19 | GSE7778 | GEO
Project description:Total RNA was extracted from the basal epidermis derived from UVB-irradiated P2.5 normal (Mc1r+/Mc1r+; Kit+/Kit+), Mc1r-mutant (Mc1re/Mc1re) and Kit-mutant (Kit/W-v/Kit/W-v) mice. Biological replicates (cy5) were labelled and co-hybridized with a reference RNA sample (cy3) to a 35K mouse cDNA microarray.
2007-05-11 | E-SMDB-3976 | biostudies-arrayexpress
Project description:Ultraviolet B (UVB) radiation is a major contributor to skin photo-ageing. Although mainly absorbed by the epidermis, UVB photons managing to penetrate the upper dermis affect human dermal fibroblasts (HDFs), leading, among others, to the accumulation of senescent cells. In vitro studies have shown that repeated exposures to subcytotoxic UVB radiation doses provoke HDFs’ premature senescence shortly after the end of the treatment period. Here, we found that repetitive exposures to non-cytotoxic UVB radiation doses after several days lead to mixed cultures, containing both senescent cells and fibroblasts resisting senescence. “Resistant” fibroblasts were more resilient to a novel intense UVB radiation stimulus. RNA-seq analysis revealed that ERCC6, encoding Cockayne syndrome group B (CSB) protein, is upregulated in resistant HDFs compared to young and senescent cells, also confirmed at the protein level. CSB was found to be a key molecule conferring protection towards UVB cytotoxicity, as siRNA-mediated CSB loss-of-expression rendered HDFs significantly more susceptible to a high UVB radiation dose. In accordance, cells from a CSB-deficient patient were found to be dramatically more photosensitive. UVB-resistant HDFs remained normal (able to undergo replicative senescence) and non-tumorigenic. Even though they formed a distinct population in-between young and senescent cells, resistant HDFs retained numerous tissue-impairing characteristics of the senescence-associated secretory phenotype, including increased matrix metalloprotease activity and promotion of epidermoid tumor xenografts in immunodeficient mice. Collectively, here we describe a novel subpopulation of HDFs showing increased resistance to UVB-mediated premature senescence, as well as undesirable traits that may negatively affect skin homeostasis.
2025-03-19 | GSE268564 | GEO
Project description:Psoriasis is a common chronic inflammatory and hyperproliferative immune-mediated skin disorder. Narrow-band UVB (NB-UVB) phototherapy is a convenient first-line treatment of psoriasis, though the mechanisms underlying its efficacy have not been completely elucidated. In order to improve our understanding of NB-UVB phototherapy, gene expression profiling was used to characterize gene expression in lesional epidermis from psoriasis patients undergoing NB-UVB phototherapy. Increased expression of melanogenesis pathway genes was observed to be the earliest response. At the end of treatment, genes involved in diverse biological processes were affected, such as pigmentation, cell adhesion, ectodermal development and metabolism. The relationship between gene expression and treatment outcome was further studied using Partial Least Squares Discriminant Analysis (PLS-DA). Gene ontology analysis showed that genes responding to phototherapy and highly correlated to treatment outcome were involved in oxidation reduction, growth and mitochondria organization. In particular SPATA18, a key regulator of mitochondria quality, was found to be significantly downregulated in psoriasis, and its upregulation following phototherapy was required for optimal clinical improvement. Our data suggest that oxidation reduction is a critical event for the resolution of psoriatic plaques. Twelve patients diagnosed with plaque type psoriasis were recruited to the study. NB-UVB irradiation was administered to the whole body two to three times a week. Treatment comprising approximately 24 sessions was given during two to three months. A total of six 4 mm diameter punch biopsies were taken from lesions on each psoriasis patient: two prior to UV treatment (pre-UV), two at the middle stage of UV treatment (after about one month of treatment, mid-UV) and two before the last treatment session (post-UV). Twelve healthy age-, sex- and skin type-matched volunteers were also recruited and two punch biopsies were taken from the buttocks. RNA was extracted from Laser capture microdissected epidermis.
2013-12-23 | E-GEOD-53431 | biostudies-arrayexpress
Project description:Aging is a physiological process characterized by a progressive decline of biological functions and an increase in destructive processes in cells and organs. Physical activity and exercise positively affects the expression of skeletal muscle markers involved in longevity pathways. Recently, a new mechanism, autophagy, was introduced to the adaptations induced by acute and chronic exercise as responsible of positive metabolic modification and health-longevity promotion. However, the molecular mechanisms regulating autophagy in response to physical activity and exercise are sparsely described. We investigated the long-term adaptations resulting from lifelong recreational football training on the expression of skeletal muscle markers involved in autophagy signaling. We demonstrated that lifelong football training increased the expression of messengers: RAD23A, HSPB6, RAB1B, TRAP1, SIRT2 and HSBPB1, involved in the auto-lysosomal and proteasome-mediated protein degradation machinery; of RPL1, RPL4, RPL36, MRLP37, involved in cellular growth and differentiation processes; of the Bcl-2, HSP70, HSP90, PSMD13 and of the ATG5-ATG12 protein complex, involved in proteasome promotion and autophagy processes in muscle samples from lifelong trained subjects compared to age-matched untrained controls. In conclusion, our results indicated that lifelong football training positively influence exercise-induced autophagy processes and protein quality control in skeletal muscle, thus promoting healthy aging. The aim of the present research was to investigate, through a differential transcriptomic approach, the effects of lifelong recreational football training on the expression of key markers involved in the autophagy response for the maintenance of protein quality control, related to healthy longevity promotion, in skeletal muscle from VPG compared to elderly untrained control subjects.
2019-03-12 | GSE125830 | GEO
Project description:Considering that human skin cancer is predominantly attributed to UV radiation from sunlight, additional investigations are needed to elucidate the role of P2RY6 in UVB-induced skin carcinogenesis. Surprisingly, we find that P2ry6 deletion exhibits marked promotion to UVB-induced skin papilloma formation compared with wild-type mice, suggesting its tumor-suppressive role in UVB-induced skin cancer. Additionally, P2ry6 knockout promotes mouse skin hyperplasia induced by short-term UVB irradiation, while UDP, the ligand of P2RY6, can inhibit UVB-induced skin damage. Furthermore, UVB irradiation can significantly upregulate P2RY6 expression in mouse and human skin cells. These results indicate that P2RY6 plays a crucial protective role in resisting UVB-induced skin damage and carcinogenesis. At the molecular level, P2RY6 deletion inhibits ubiquitination and expression of XPC after UVB irradiation in keratinocytes, resulting in the accumulation of CPDs (cyclobutane pyrimidine dimers). P2RY6 deletion also activates PI3K/AKT signaling pathway in vitro and in vivo. The CPD accumulation and inflammatory responses enhanced by P2RY6 deletion are reversed by an AKT inhibitor. These findings suggest that P2RY6 acts as a tumor suppressor in UVB-induced skin cancer by regulating PI3K/AKT signaling pathway.
2024-01-16 | GSE251675 | GEO
Project description:Psoriasis is a common chronic inflammatory and hyperproliferative immune-mediated skin disorder. Narrow-band UVB (NB-UVB) phototherapy is a convenient first-line treatment of psoriasis, though the mechanisms underlying its efficacy have not been completely elucidated. In order to improve our understanding of NB-UVB phototherapy, gene expression profiling was used to characterize gene expression in lesional epidermis from psoriasis patients undergoing NB-UVB phototherapy. Increased expression of melanogenesis pathway genes was observed to be the earliest response. At the end of treatment, genes involved in diverse biological processes were affected, such as pigmentation, cell adhesion, ectodermal development and metabolism. The relationship between gene expression and treatment outcome was further studied using Partial Least Squares Discriminant Analysis (PLS-DA). Gene ontology analysis showed that genes responding to phototherapy and highly correlated to treatment outcome were involved in oxidation reduction, growth and mitochondria organization. In particular SPATA18, a key regulator of mitochondria quality, was found to be significantly downregulated in psoriasis, and its upregulation following phototherapy was required for optimal clinical improvement. Our data suggest that oxidation reduction is a critical event for the resolution of psoriatic plaques.
2013-12-23 | GSE53431 | GEO
Project description:While several physiological skin parameters vary in a circadian manner, the identity of genes participating in chronobiology of skin remains unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle related genes, the former peaking during the day and the latter peaking at the night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes as keratinocyte-specific deletion of Bmal1 obliterates time of day dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. Consistent with higher cellular susceptibility to UV-induced DNA damage during S phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. As maximum numbers of keratinocytes go through S phase in the late afternoon in the human epidermis, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation such that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers.
2012-08-02 | GSE38623 | GEO