title: PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine.
abstract: Recent studies have shown that DNA demethylation goes through the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by Tet proteins. However, it is still unclear how the target regions for demethylation are distinguished within their genomic context. Here we show that the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) has the ability to direct local demethylation around its binding sites, the PPAR response elements (PPREs), during adipocyte differentiation. PPARγ is a key regulator of the differentiation process that forms a PPARγ co-activator complex on PPREs and activates the expression of adipocyte-specific genes. The complex is poly(ADP-ribosyl)ated (PARylated) on PPREs, and Tet proteins catalyse the conversion of 5mC to 5hmC locally by their ability to bind to the PAR polymer, thereby inducing region-specific demethylation. Our study demonstrates that a sequence-dependent transcription factor complex can, through its post-translational modification, serve for Tet proteins as a landmark to identify sites of DNA demethylation.
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Fujiki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Shinoda
authors.forename: Fumi
authors.initials: F
authors.lastname: Kano
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Sato
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.forename: Masayuki
authors.initials: M
authors.lastname: Murata
mesh_terms: D041721:3T3-L1 Cells; D044503:5-Methylcytosine / Q000031:analogs & derivatives; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D020218:Response Elements / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D047495:PPAR gamma; D010616:Phenanthrenes; D011518:Proto-Oncogene Proteins; C540839:TET1 protein, mouse; C011865:5-hydroxymethylcytosine; D011064:Poly Adenosine Diphosphate Ribose; D044503:5-Methylcytosine; D003596:Cytosine