dna methyltransferase controls stem cell aging by regulating bmi1 and ezh2 through micrornasdna甲基转移酶控制干细胞衰老调节bmi1和ezh2通过小分子核糖核酸.pdfVIP

DNA Methyltransferase Controls Stem Cell Aging by Regulating BMI1 and EZH2 through MicroRNAs Ah-Young So1,2,3., Ji-Won Jung4., Seunghee Lee1,2,3., Hyung-Sik Kim 1,2,3, Kyung-Sun Kang1,2,3* 1 Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea, 2 Department of Veterinary Public Health, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea, 3 Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea, 4 Division of Intractable Diseases, Center for Biomedical Sciences, Korea National Institute of Health, Chungbuk, Republic of Korea Abstract Epigenetic regulation of gene expression is well known mechanism that regulates cellular senescence of cancer cells. Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the cellular senescence of human umbilical cord blood-derived multipotent stem cells (hUCB-MSCs) and increased p16INK4A and p21CIP1/WAF1 expression. DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16INK4A and p21CIP1/WAF1 promoter regions. Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16INK4A and CIP1/WAF1 p21 promoter regions. We found that DNMT inhibition decreased expression levels of Polycomb-group (PcG) proteins and increased expression of microRNAs (miRNAs), which target PcG proteins. Decreased CpG island methylation and increased levels of active histone marks at genomic regions encoding miRNAs were observed after 5-AzaC treatment. Taken together, DNMTs have a critical role in regulating the cellular senesc