title: Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity.
abstract: More than one-half billion people are obese, and despite progress in genetic research, much of the heritability of obesity remains enigmatic. Here, we identify a Trim28-dependent network capable of triggering obesity in a non-Mendelian, "on/off" manner. Trim28(+/D9) mutant mice exhibit a bi-modal body-weight distribution, with isogenic animals randomly emerging as either normal or obese and few intermediates. We find that the obese-"on" state is characterized by reduced expression of an imprinted gene network including Nnat, Peg3, Cdkn1c, and Plagl1 and that independent targeting of these alleles recapitulates the stochastic bi-stable disease phenotype. Adipose tissue transcriptome analyses in children indicate that humans too cluster into distinct sub-populations, stratifying according to Trim28 expression, transcriptome organization, and obesity-associated imprinted gene dysregulation. These data provide evidence of discrete polyphenism in mouse and man and thus carry important implications for complex trait genetics, evolution, and medicine.
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Dalgaard
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, 04103 Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Landgraf
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Heyne
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Lempradl
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: John
authors.initials: J
authors.lastname: Longinotto
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Gossens
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Ruf
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,1030 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Orthofer
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Strogantsev
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Madhan
authors.initials: M
authors.lastname: Selvaraj
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Tess Tsai-Hsiu
authors.initials: TT
authors.lastname: Lu
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer (IMPPC) and Josep Carreras Leukaemia Research Institute, Can Ruti Campus, Ctra de Can Rutí, Cami de les Escoles s/n, Badalona 08916, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Casas
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Teperino
authors.affiliation: Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK; Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 3EG, UK.
authors.forename: M Azim
authors.initials: MA
authors.lastname: Surani
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Ilona
authors.initials: I
authors.lastname: Zvetkova
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Debra
authors.initials: D
authors.lastname: Rimmington
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Y C Loraine
authors.initials: YC
authors.lastname: Tung
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Lam
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Larder
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Giles S H
authors.initials: GS
authors.lastname: Yeo
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.affiliation: Institute for Predictive and Personalized Medicine of Cancer (IMPPC) and Josep Carreras Leukaemia Research Institute, Can Ruti Campus, Ctra de Can Rutí, Cami de les Escoles s/n, Badalona 08916, Barcelona, Spain.
authors.forename: Tanya
authors.initials: T
authors.lastname: Vavouri
authors.affiliation: Department of Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Melbourne, VIC 3086, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Whitelaw
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences,1030 Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jenuwein
authors.affiliation: Department of Pharmacology and Pharmacy, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong.
authors.forename: Ching-Lung
authors.initials: CL
authors.lastname: Cheung
authors.affiliation: Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
authors.affiliation: University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Coll
authors.affiliation: Department of Women's and Child Health, Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, 04103 Leipzig, Germany; Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Körner
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany. Electronic address: pospisilik@ie-freiburg.mpg.de.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Pospisilik
mesh_terms: D000293:Adolescent; D000818:Animals; D015992:Body Mass Index; D002648:Child; D002675:Child, Preschool; D044127:Epigenesis, Genetic; D057895:Haploinsufficiency; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D009749:Nutrition Surveys; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic; D012097:Repressor Proteins / Q000235:genetics*; D013851:Thinness / Q000235:genetics*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D009687:Nuclear Proteins; D012097:Repressor Proteins; C101116:TRIM28 protein, human; C103190:Trim28 protein, mouse; D000076183:Tripartite Motif-Containing Protein 28
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