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  Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Dalgaard, K., Landgraf, K., Heyne, S., Lempradl, A., Longinotto, J., Gossens, K., et al. (2016). Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell, 164, 353-364. doi:doi: 10.1016/j.cell.2015.12.025.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-AF2F-C Version Permalink: http://hdl.handle.net/21.11116/0000-0005-C2CE-8
Genre: Journal Article

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https://www.ncbi.nlm.nih.gov/pubmed/26824653 (Publisher version)
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 Creators:
Dalgaard, Kevin1, 2, Author
Landgraf, Kathrin3, 4, Author
Heyne, Steffen1, Author
Lempradl, Adelheid1, Author
Longinotto, John1, Author
Gossens, Klaus1, Author
Ruf, Marius1, Author
Orthofer, Michael5, Author
Strogantsev, Ruslan6, Author
Selvaraj, Madhan1, Author
Lu, Tess Tsai-Hsiu1, Author
Casas, Eduard7, Author
Teperino, Raffaele1, 8, Author
Surani, M. Azim9, 10, 11, Author
Zvetkova, Ilona12, Author
Rimmington, Debra12, Author
Tung, Y.C. Loraine12, Author
Lam, Brian12, Author
Larder, Rachel12, Author
Yeo, Giles S.H.12, Author
O’Rahilly, Stephen12, AuthorVavouri, Tanya7, AuthorWhitelaw, Emma13, AuthorPenninger, Josef M.5, AuthorJenuwein, Thomas1, Author              Cheung, Ching-Lung14, AuthorFerguson-Smith, Anne C.6, AuthorColl, Anthony P.12, AuthorKörner, Antje3, 4, AuthorPospisilik, John Andrew1, Author               more..
Affiliations:
1Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              
2Nord Nordisk A/S, Malov, Denmark, ou_persistent22              
3Department of Women's and Child Health, Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, University of Leipzig, Leipzig, Germany, ou_persistent22              
4Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany, ou_persistent22              
5IMBA, Institute of molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria, ou_persistent22              
6Department of Genetics, University of Cambridge, Cambridge, UK, ou_persistent22              
7Institute for Predictive and Personalized Medicine of Cancer (IMPPC) and Josep Carreras Leukaemia Research Institute, Can Ruti Campus, Barcelona, Spain, ou_persistent22              
8Institute of Experimental Genetics, Helmholtz Zentrum Muenchen and German Center for Diabetes Research /DZD), Neuherber, Germany, ou_persistent22              
9Wellcome Trust Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK, ou_persistent22              
10Department of Physiology, Development and Neuroscienc, University of Cambridge, Cambridge, UK, ou_persistent22              
11Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Cambridge, UK, ou_persistent22              
12University of Cambrdige metabolic Research Laboratories and MRC Metabolic Diseases Unit, Welcome Trust-MRC Institute of Metabolic Science, Cambridge, UK, ou_persistent22              
13Department of Genetics, La Trobe Institute for Molecular Science, La Trobe University , Melbourne, Australia, ou_persistent22              
14Department of Pharmacology and Pharmacy, Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2016-01-28
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: doi: 10.1016/j.cell.2015.12.025
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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 164 Sequence Number: - Start / End Page: 353 - 364 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183