title: Epigenetic and genetic dissections of UV-induced global gene dysregulation in skin cells through multi-omics analyses.
abstract: To elucidate the complex molecular mechanisms underlying the adverse effects UV radiation (UVR) on skin homeostasis, we performed multi-omics studies to characterize UV-induced genetic and epigenetic changes. Human keratinocytes from a single donor treated with or without UVR were analyzed by RNA-seq, exome-seq, and H3K27ac ChIP-seq at 4 h and 72 h following UVR. Compared to the relatively moderate mutagenic effects of UVR, acute UV exposure induced substantial epigenomic and transcriptomic alterations, illuminating a previously underappreciated role of epigenomic and transcriptomic instability in skin pathogenesis. Integration of the multi-omics data revealed that UVR-induced transcriptional dysregulation of a subset of genes was attributable to either genetic mutations or global redistribution of H3K27ac. H3K27ac redistribution further led to the formation of distinctive super enhancers in UV-irradiated cells. Our analysis also identified several new UV target genes, including CYP24A1, GJA5, SLAMF7 and ETV1, which were frequently dysregulated in human squamous cell carcinomas, highlighting their potential as new molecular targets for prevention or treatment of UVR-induced skin cancers. Taken together, our concurrent multi-omics analyses provide new mechanistic insights into the complex molecular networks underlying UV photobiological effects, which have important implications in understanding its impact on skin homeostasis and pathogenesis.
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Dermatology, Columbia University, New York, NY, USA.
authors.forename: Milda
authors.initials: M
authors.lastname: Stanislauskas
authors.affiliation: Department of Biostatistics, Columbia University, New York, NY, USA.
authors.forename: Gen
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA.|Department of Neurology, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Dermatology, Columbia University, New York, NY, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
mesh_terms: D000107:Acetylation; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D061251:Primary Cell Culture; D040901:Proteomics / Q000379:methods; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D014466:Ultraviolet Rays / Q000009:adverse effects*; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000073359:Exome Sequencing; D000097003:Gap Junction alpha-5 Protein
chemical_list: D017630:Connexins; D004268:DNA-Binding Proteins; D006657:Histones; D000071176:Signaling Lymphocytic Activation Molecule Family; D014157:Transcription Factors; D065668:Vitamin D3 24-Hydroxylase; D000097003:Gap Junction alpha-5 Protein; C095239:ETV1 protein, human; C448987:SLAMF7 protein, human; C585549:CYP24A1 protein, human