Integrated transcriptome-epigenome analysis identifies NRIP1, PRDM1, and OSGIN2 as key regulators in skin aging

Summary: Abstract Body: Epigenetic modifications are increasingly recognized as critical regulators of the aging process, particularly in skin aging. These modifications can activate or suppress genes associated with collagen production, oxidative stress responses, and inflammation, thereby contributing to the acceleration of skin aging. Here, we performed integrated transcriptome-epigenome analyses (RNA-Seq, ATAC-Seq, and ChIP-Seq) in primary human dermal fibroblasts (HDFs) overexpressing DNMT1. DNMT1 overexpression in skin cells resulted in significant alterations in genes such as NRIP1, OSGIN2, and CRAT. In the promoter region analysis, significant changes were observed in inflammation- and immunity-related genes, including PRDM1. Furthermore, we validated the expression of core genes NRIP1, PRDM1, OSGIN2 (upregulated), and CRAT (downregulated) in ultraviolet (UV)-irradiated HDFs and skin tissues. Knockdown of NRIP1, PRDM1, or OSGIN2 resulted in reduced matrix metalloproteinase (MMP)-1 levels, which are typically elevated following UV irradiation, along with restored procollagen levels. In contrast, overexpression of NRIP1, PRDM1, or OSGIN2 led to a significant increase in the expression of pro-inflammatory cytokines and MMPs. Interestingly, NRIP1 knockdown caused a subsequent decrease in PRDM1 and OSGIN2 expression, whereas NRIP1 overexpression resulted in the upregulation of PRDM1 and OSGIN2 expression. In skin-specific Dnmt1 conditional knockout (cKO) mice, reduced inflammatory cytokines and aging phenotypes were observed upon acute UV irradiation, thereby validating the efficacy of our skin aging model through DNMT1 regulation in vivo. Yidan Cui^{1, 2, 3}, Ji Hwan Moon⁴, Hye Sun Shin¹, Min-Kyoung Kim^{1, 3}, Donghun Lee^{1, 2, 3} 1. Department of Dermatology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea (the Republic of). 2. Seoul National University Graduate School Department of Biomedical Science, Seoul, Seoul, Korea (the Republic of). 3. Institute of Human-Environment Interface Biology, Medical Research Center, Seoul National University, Seoul, Korea (the Republic of). 4. Samsung Medical Center Samsung Genome Institute, Gangnam-gu, Seoul, Korea (the Republic of). Genetic Disease, Gene Regulation, Gene Therapy & Epigenetics