title: Poly(ADP-ribose)polymerase-1 (PARP1) controls adipogenic gene expression and adipocyte function.
abstract: Poly(ADP-ribose)polymerase-1 (PARP1) is a chromatin-associated enzyme that was described to affect chromatin compaction. Previous reports suggested a dynamic modulation of the chromatin landscape during adipocyte differentiation. We thus hypothesized that PARP1 plays an important transcriptional role in adipogenesis and metabolism and therefore used adipocyte development and function as a model to elucidate the molecular action of PARP1 in obesity-related diseases. Our results show that PARP1-dependent ADP-ribose polymer (PAR) formation increases during adipocyte development and, at late time points of adipogenesis, is involved in the sustained expression of PPARγ2 and of PPARγ2 target genes. During adipogenesis, PARP1 was recruited to PPARγ2 target genes such as CD36 or aP2 in a PAR-dependent manner. Our results also reveal a PAR-dependent decrease in repressory histone marks (e.g. H3K9me3) and an increase in stimulatory marks (e.g. H3K4me3) at the PPARγ2 promoter, suggesting that PARP1 may exert its regulatory function during adipogenesis by altering histone marks. Interestingly, activation of PARP1 enzymatic activity was prevented with a topoisomerase II inhibitor. These data hint at topoisomerase II-dependent, transient, site-specific double-strand DNA breaks as the cause for poly(ADP)-ribose formation, adipogenic gene expression, and adipocyte function. Together, our study identifies PARP1 as a critical regulator of PPARγ2-dependent gene expression with implications in adipocyte function and obesity-related disease models.
authors: Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.
authors: Süheda
authors: S
authors: Erener
authors: Mareike
authors: M
authors: Hesse
authors: Radina
authors: R
authors: Kostadinova
authors: Michael O
authors: MO
authors: Hottiger
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D013858:Thiobarbiturates / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D014158:Transcription, Genetic
chemical_list: D018955:CD36 Antigens; D002843:Chromatin; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D006657:Histones; D047495:PPAR gamma; D034741:RNA, Small Interfering; D013858:Thiobarbiturates; D059005:Topoisomerase II Inhibitors; D000246:Adenosine Diphosphate Ribose; D004247:DNA; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C045459:merbarone