title: Microrna-217 modulates human skin fibroblast senescence by directly targeting DNA methyltransferase 1.
abstract: DNA methyltransferase 1 (DNMT1) is a major epigenetic regulator associated with many biological processes. However, the roles and mechanisms of DNMT1 in skin aging are incompletely understood. Here we explored the role of DNMT1 in human skin fibroblasts senescence and its related regulatory mechanisms. DNMT1 expression decreased in passage-aged fibroblasts and DNMT1 silencing in young fibroblasts induced the senescence phenotype. MiR-217 is predicted to target DNMT1 mRNA and miR-217 expression increased in passage-aged fibroblasts. MiR-217 directly targeted the 3'-untranslated region (3'-UTR) of DNMT1 in HEK 293T cells and inhibited DNMT1 expression in fibroblasts. MiR-217 overexpression induced a senescence phenotype in young fibroblasts, and miR-217 downregulation in old HSFs partially reversed the senescence phenotype. However, these effects could be significantly rescued by regulating DNMT1 expression in fibroblasts. After regulating miR-217 levels, we analyzed changes in the promoter methylation levels of 24 senescent-associated genes, finding that 6 genes were significantly altered, and verified p16 and phosphorylated retinoblastoma (pRb) protein levels. Finally, an inverse correlation between DNMT1 and miR-217 expression was observed in skin tissues and different-aged fibroblasts. Together, these findings revealed that miR-217 promotes fibroblasts senescence by suppressing DNMT1-mediated methylation of p16 and pRb by targeting the DNMT1 3'-UTR.
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.|Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ben
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Du
authors.affiliation: Department of Dermatology, Hunan Provincial People's Hospital, Changsha, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Zhi-Li
authors.initials: ZL
authors.lastname: Deng
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Jian
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Hong-Fu
authors.initials: HF
authors.lastname: Xie
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.|Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China.|Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000367:Age Factors; D000368:Aged; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics*; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016161:Genes, Retinoblastoma; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D035683:MicroRNAs / Q000235:genetics*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012867:Skin / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D019941:Cyclin-Dependent Kinase Inhibitor p16; C553315:MIRN217 microRNA, human; D035683:MicroRNAs; D000076123:DNA (Cytosine-5-)-Methyltransferase 1
keywords: DNMT1; miR-217; senescence; skin aging