title: Role of PRDM16 and its PR domain in the epigenetic regulation of myogenic and adipogenic genes during transdifferentiation of C2C12 cells.
abstract: The positive regulatory domain containing 16 (PRDM16) is commonly regarded as a "switch" controlling the transdifferentiation of myoblasts to brown adipocytes. The N-positive regulatory (PR) domain, which is highly homologous to SET domain, is a characteristic structure for the PRDM family. Many SET domain containing proteins and several PRDM members have been found to possess histone methyltransferase activity, yet the role of PRDM16 and its PR domain in the epigenetic regulation of myogenic and adipogenic genes during myoblasts/adipocytes transdifferentiation remains unexplored. In this study, we transfected C2C12 myoblasts to stably express PRDM16 and observed the repression of myogenic genes and activation of adipogenic genes at both proliferation and differentiation stages. Ectopic PRDM16-induced reprogramming of myogenic and adipogenic genes was associated with the hypermethylation on some CpG sites in the enhancer or promoter of MyoD and myogenin, but the methylation status of PPARγ promoter was not affected. C2C12 cells expressing truncated PRDM16 lacking PR domain (ΔPR-PRDM16) demonstrated attenuation of both adipogenic and myogenic potentials, indicated by PPARγ inactivation and decreased triglyceride deposition, as well as a downregulation of MyoD, MyHC and MCK genes, as compared with C2C12 cells expressing intact PRDM16. Furthermore, C2C12 cells expressing ΔPR-PRDM16 exhibited significant differences in histone modifications on the promoters of MyoD and PPARγ genes. Taken together, PRDM16-induced C2C12 transdifferentiation is associated with alterations in CpG methylation of myogenic factors, and PR domain affects both myogenesis and adipogenesis with modified histone methylation marks on MyoD and PPARγ promoters.
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China; College of Animal Science and Technology, Northwest A & F University, Shaanxi, Yangling 712100, PR China. Electronic address: nicelixiao@nwsuaf.edu.cn.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China; College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, PR China. Electronic address: wangjinquan163@163.com.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address: zhengjennyjiang@gmail.com.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address: guofeng034@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.affiliation: Division of Nutritional Sciences, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY 14853, United States. Electronic address: soloway@cornell.edu.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Soloway
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address: zhao.ruqian@gmail.com.
authors.forename: Ruqian
authors.initials: R
authors.lastname: Zhao
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic; D051379:Mice; D009132:Muscles / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C521133:Prdm16 protein, mouse; D014157:Transcription Factors
keywords: Adipogenesis; C2C12 ce; DNA and histone methylation; Myogenesis; PR domain; PRDM16