Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity
Lu, Tess Tsai-Hsiu
Surani, M. Azim
Tung, Y.C. Loraine
Yeo, Giles S.H.
Penninger, Josef M.
Ferguson-Smith, Anne C.
Coll, Anthony P.
Pospisilik, J. Andrew
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Dalgaard, K., Landgraf, K., Heyne, S., Lempradl, A., Longinotto, J., Gossens, K., Ruf, M., et al. (2016). Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell, 164 (3), 353-364. https://doi.org/10.1016/j.cell.2015.12.025
This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.cell.2015.12.025
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. [Plus video and graphical abstract - see webpage]
This work was supported by funding from the Max-Planck Society, ERC (ERC-StG-281641), DFG (SFB992 “MedEp”; SFB 1052 “ObesityMechanisms”), EU_FP7 (NoE ”Epigenesys”; “Beta-JUDO” n° 279153), BMBF (DEEP), MRC (Metabolic Disease Unit - APC, SOR, GSHY, MRC_MC_UU_12012/1), Wellcome Trust (SOR, 095515/Z/11/Z), and the German Research Council (DFG) for the Clinical Research Center “Obesity Mechanisms” CRC1052/1 C05 and the Federal Ministry of Education and Research, Germany, FKZ, 01EO1001 (Integrated Research and Treatment Center [IFB] Adiposity Diseases).
External DOI: https://doi.org/10.1016/j.cell.2015.12.025
This record's URL: https://www.repository.cam.ac.uk/handle/1810/253549
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/