Abstract
The simultaneous analysis of different regulatory levels of biological phenomena by means of multi-omics data integration has proven an invaluable tool in modern precision medicine, yet many processes ultimately paving the way towards disease manifestation remain elusive and have not been studied in this regard. Here we investigated the early molecular events following repetitive UV irradiation of in vivo healthy human skin in depth on transcriptomic and epigenetic level. Our results provide first hints towards an immediate acquisition of epigenetic memories related to aging and cancer and demonstrate significantly correlated epigenetic and transcriptomic responses to irradiation stress. The data allowed the precise prediction of inter-individual UV sensitivity, and molecular subtyping on the integrated post-irradiation multi-omics data established the existence of three latent molecular phototypes. Importantly, further analysis suggested a form of melanin-independent DNA damage protection in subjects with higher innate UV resilience. This work establishes a high-resolution molecular landscape of the acute epidermal UV response and demonstrates the potential of integrative analyses to untangle complex and heterogeneous biological responses.
Highlights
The simultaneous analysis of different regulatory levels of biological phenomena by means of multi-omics data integration has proven an invaluable tool in modern precision medicine, yet many processes paving the way towards disease manifestation remain elusive and have not been studied in this regard
In order to obtain a comprehensive picture of the molecular events regulating acute epidermal photobiology, 32 female Caucasian volunteers (Fitzpatrick phototypes 1–4) where irradiated with individually calibrated doses of 0.9 minimal erythema dose (MED) using a full spectrum solar simulator on three subsequent days on a sun-protected area on their lower backs. 24 h after the last irradiation, suction blister roofs were extracted from irradiated and control sites of each subject and gene expression profiling (Illumina RNA seq) and concomitant DNA methylation profiling (Illumina EPIC Arrays) were performed
Paired differential expression and methylation analyses between irradiated and control areas revealed that in total 20.5% (FDR < 0.05) of all interrogated CpGs and 32.4% (FDR < 0.05) of all detected gene transcripts were significantly altered in response to irradiation. These considerable changes were spread over the whole genome, with notable exceptions only occurring in the regions around the centromeres and in some constitutively heterochromatic regions e.g. on chromosome 13 (Fig. 1a)
Summary
The simultaneous analysis of different regulatory levels of biological phenomena by means of multi-omics data integration has proven an invaluable tool in modern precision medicine, yet many processes paving the way towards disease manifestation remain elusive and have not been studied in this regard. Human skin has developed several defense systems to guard against the damaging effects of UV: Prominently these include structural changes to the tissue such as epidermal thickening and the synthesis of melanin, but they comprise quick molecular adaptations like the suspension of cell cycle and gene transcription, as well as the activation of DNA repair pathways. A multi-omics analysis of UV irradiated keratinocytes recently identified several new UV target genes including CYP24A1, GJA5, SLAMF7 and E TV118, demonstrating the value of multi-layered omics analyses in unraveling biological phenomena and enabling more reliable biomarker detection, as it has been shown in cancer research, allowing molecular diagnosis and prognosis, often utilizing DNA methylation m arkers[19,20]
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