title: MicroRNA-26a targets ten eleven translocation enzymes and is regulated during pancreatic cell differentiation.
abstract: Ten eleven translocation (TET) enzymes (TET1/TET2/TET3) and thymine DNA glycosylase (TDG) play crucial roles in early embryonic and germ cell development by mediating DNA demethylation. However, the molecular mechanisms that regulate TETs/TDG expression and their role in cellular differentiation, including that of the pancreas, are not known. Here, we report that (i) TET1/2/3 and TDG can be direct targets of the microRNA miR-26a, (ii) murine TETs, especially TET2 and TDG, are down-regulated in islets during postnatal differentiation, whereas miR-26a is up-regulated, (iii) changes in 5-hydroxymethylcytosine accompany changes in TET mRNA levels, (iv) these changes in mRNA and 5-hydroxymethylcytosine are also seen in an in vitro differentiation system initiated with FACS-sorted adult ductal progenitor-like cells, and (v) overexpression of miR-26a in mice increases postnatal islet cell number in vivo and endocrine/acinar colonies in vitro. These results establish a previously unknown link between miRNAs and TET expression levels, and suggest a potential role for miR-26a and TET family proteins in pancreatic cell differentiation.
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, The Irell and Manella Graduate School of Biological Sciences, and Transgenic Mouse Core, Beckman Research Institute of City of Hope, Duarte, CA 91010.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Fu
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.forename: Xichun
authors.initials: X
authors.lastname: Wang
authors.forename: Angela
authors.initials: A
authors.lastname: Luo
authors.forename: Junkai
authors.initials: J
authors.lastname: Hu
authors.forename: Xianwu
authors.initials: X
authors.lastname: Zheng
authors.forename: Walter M
authors.initials: WM
authors.lastname: Tsark
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.forename: Hsun Teresa
authors.initials: HT
authors.lastname: Ku
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D003596:Cytosine / Q000031:analogs & derivatives; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D044127:Epigenesis, Genetic / Q000502:physiology*; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D007515:Islets of Langerhans / Q000201:enzymology / Q000502:physiology*; D008156:Luciferases; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D044085:Microfluidics; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D044502:Thymine DNA Glycosylase / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D035683:MicroRNAs; C543693:Mirn26 microRNA, mouse; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D008156:Luciferases; D044502:Thymine DNA Glycosylase
keywords: 5hmC; DNA methyaltion; epigenetics; posttranscriptional regulation; stem cell