title: Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling.
abstract: Rapamycin and its derivatives are mTOR inhibitors used in tissue transplantation and cancer therapy. A percentage of patients treated with these inhibitors develop diabetic-like symptoms, but the molecular mechanisms are unknown. We show here that chronic rapamycin treatment in mice led to insulin resistance with suppression of insulin/IGF signaling and genes associated within this pathway, such as Igf1-2, Irs1-2, and Akt1-3. Importantly, skeletal muscle-specific YY1 knockout mice were protected from rapamycin-induced diabetic-like symptoms. This protection was caused by hyperactivation of insulin/IGF signaling with increased gene expression in this cascade that, in contrast to wild-type mice, was not suppressed by rapamycin. Mechanistically, rapamycin induced YY1 dephosphorylation and recruitment to promoters of insulin/IGF genes, which promoted interaction with the polycomb protein-2 corepressor. This was associated with H3K27 trimethylation leading to decreased gene expression and insulin signaling. These results have implications for rapamycin action in human diseases and biological processes such as longevity.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Blättler
authors.forename: John T
authors.initials: JT
authors.lastname: Cunningham
authors.forename: Francisco
authors.initials: F
authors.lastname: Verdeguer
authors.forename: Helen
authors.initials: H
authors.lastname: Chim
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.forename: Huifei
authors.initials: H
authors.lastname: Liu
authors.forename: Klaas
authors.initials: K
authors.lastname: Romanino
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005786:Gene Expression Regulation / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D050986:YY1 Transcription Factor / Q000172:deficiency* / Q000378:metabolism
chemical_list: D006657:Histones; D007328:Insulin; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse; D007334:Insulin-Like Growth Factor I; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D008239:Lysine; D020123:Sirolimus