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Cited by 190Genetic Syndromes and ImprintingEpigenetics and DNA MethylationGenetic Associations and Epidemiology

Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity

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Dalgaard, Kevin, Landgraf, Kathrin, Heyne, Steffen, Lempradl, Adelheid, Longinotto, John, Gossens, Klaus, Ruf, Marius, Orthofer, Michael +22 more·2016·Cell
DOI 10.1016/j.cell.2015.12.025PMC PMC4735019
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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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  • Inbred laboratory mice raised in standardized conditions display high phenotypic trait variability and are prone to polyphenism.

    “Inbred laboratory mice raised in standardized conditions nevertheless keep displaying high phenotypic trait variability (Gartner, 1990; Tuttle et al, 2018) and are prone to polyphenism, that is, several discrete phenotypes on the same genetic background (Dalgaard et al, 2016; Yang et al, 2022).”

    From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Dalgaard et al, 2016

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References 62 · Cited by 190

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Authors
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. C. L., Lam, B., Larder, R., Yeo, G. S. H., 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.
Affiliations
  • Max Planck Institute of Immunobiology and Epigenetics (DE)
  • University Hospital Leipzig (DE)
  • Institute of Molecular Biotechnology (AT)
  • University of Cambridge (GB)
  • Josep Carreras Leukaemia Research Institute (ES)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • La Trobe University (AU)
  • University of Hong Kong (HK)
Corresponding author
Pospisilik, J. Andrew
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2016-01
Volume
164
Issue
3
Pages
353-364
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2015.12.025
PMC
PMC4735019
OpenAlex
W2254116509
Cited by
190
References
62
Citations by year
2026: 8 · 2025: 10 · 2024: 15 · 2023: 12 · 2022: 14 · 2021: 15 · 2020: 22 · 2019: 17 · 2018: 27 · 2017: 21 · 2016: 28
FWCI
25.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion, cc-by)
  • The HKU Scholars Hub (University of Hong Kong) (submittedVersion, cc-by-nc-nd)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
Funders
  • Deutsche Forschungsgemeinschaft (CRC1052/1 C05, SFB 1052, SFB992)
  • Max-Planck-Gesellschaft (ERC-StG-281641)
  • Bundesministerium für Bildung und Forschung (01EO1001)
  • Connecticut Department of Energy and Environmental Protection (MRC_MC_UU_12012/1)
  • Wellcome Trust
  • Institut Français de Bioinformatique
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
TRIM28, haploinsufficiency, obesity, genomic imprinting, neuronatin, Peg3, CDKN1C, PLAGL1, adipose tissue transcriptome, polyphenism, heritability of obesity
MeSH terms
Tripartite Motif-Containing Protein 28, Adolescent, Animals, Child, Child, Preschool, Humans, Nuclear Proteins, Nutrition Surveys, Obesity, Polymorphism, Genetic, Repressor Proteins, Thinness, Body Mass Index, Epigenesis, Genetic, Mice, Haploinsufficiency

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