Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Dalgaard, Kevin; Landgraf, Kathrin; Heyne, Steffen; Lempradl, Adelheid; Longinotto, John; Gossens, Klaus; Ruf, Marius; Orthofer, Michael; Strogantsev, Ruslan; Selvaraj, Madhan; Lu, Tess Tsai-Hsiu; Casas, Eduard; Teperino, Raffaele; Surani, M. Azim; Zvetkova, Ilona; Rimmington, Debra; Tung, Y.C. Loraine; Lam, Brian; Larder, Rachel; Yeo, Giles S.H.; O’Rahilly, Stephen; Vavouri, Tanya; Whitelaw, Emma; Penninger, Josef M.; Jenuwein, Thomas; Cheung, Ching-Lung; Ferguson-Smith, Anne C.; Coll, Anthony P.; Körner, Antje; Pospisilik, John Andrew

doi:10.1016/j.cell.2015.12.025

Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

Dalgaard, K., Landgraf, K., Heyne, S., Lempradl, A., Longinotto, J., Gossens, K., Ruf, M., Orthofer, M., Strogantsev, R., Selvaraj, M., Lu, T.-T.-H., Casas, E., Teperino, R., Surani, M. A., Zvetkova, I., Rimmington, D., Tung, Y. L., Lam, B., Larder, R., Yeo, G. S., O’Rahilly, S., Vavouri, T., Whitelaw, E., Penninger, J. M., Jenuwein, T., Cheung, C.-L., Ferguson-Smith, A. C., Coll, A. P., Körner, A., & Pospisilik, J. A. (2016). Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell, 164, 353-364. doi:10.1016/j.cell.2015.12.025.

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アイテムのパーマリンク: https://hdl.handle.net/11858/00-001M-0000-002C-AF2F-C 版のパーマリンク: https://hdl.handle.net/21.11116/0000-0008-A5A7-1

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Dalgaard, Kevin^{1, 2}, 著者
Landgraf, Kathrin^{3, 4}, 著者
Heyne, Steffen¹, 著者
Lempradl, Adelheid¹, 著者
Longinotto, John¹, 著者
Gossens, Klaus¹, 著者
Ruf, Marius¹, 著者
Orthofer, Michael⁵, 著者
Strogantsev, Ruslan⁶, 著者
Selvaraj, Madhan¹, 著者
Lu, Tess Tsai-Hsiu¹, 著者
Casas, Eduard⁷, 著者
Teperino, Raffaele^{1, 8}, 著者
Surani, M. Azim^{9, 10, 11}, 著者
Zvetkova, Ilona¹², 著者
Rimmington, Debra¹², 著者
Tung, Y.C. Loraine¹², 著者
Lam, Brian¹², 著者
Larder, Rachel¹², 著者
Yeo, Giles S.H.¹², 著者
O’Rahilly, Stephen¹², 著者Vavouri, Tanya⁷, 著者Whitelaw, Emma¹³, 著者Penninger, Josef M.⁵, 著者Jenuwein, Thomas¹, 著者 Cheung, Ching-Lung¹⁴, 著者Ferguson-Smith, Anne C.⁶, 著者Coll, Anthony P.¹², 著者Körner, Antje^{3, 4}, 著者Pospisilik, John Andrew¹, 著者全て表示

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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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要旨: 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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言語: eng - English

日付: 出版: 2016-01-28

出版の状態: 出版

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識別子（DOI, ISBNなど）: DOI: 10.1016/j.cell.2015.12.025

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出版物名: Cell

種別: 学術雑誌

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出版社, 出版地: Cambridge, Mass. : Cell Press

ページ: - 巻号: 164 通巻号: - 開始・終了ページ: 353 - 364 識別子（ISBN, ISSN, DOIなど）: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183

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