Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity
Dalgaard K et al. (2016) Cell (http://dx.doi.org/10.1016/j.cell.2015.12.025)
Worldwide, some 600 million people are obese, yet despite progress in genetic research, much of the high heritability of obesity remains enigmatic. The worldwide consortium of researchers involved in this study has begun to shed light on an epigenetic mechanism that can control whether an individual is lean or obese.
The consortium was led by Andrew Pospisilik at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg, Germany, and included scientists in several labs across Cambridge and in many other European countries as well as in Hong Kong and Australia.
The research used mice deficient for one copy of the gene Trim28, whose weights were observed to be distributed in a bi-modal pattern - either lean, or obese, with few of intermediate size.
By comparing the global gene expression pattern in the lean and obese populations, the team uncovered a network of 'imprinted' genes - carrying paternally inherited epigenetic marks - that were expressed at significantly lower levels in the obese animals. The network includes the genes Nnat, Peg3, Cdkn1c, and Plagl1, which are known to alter growth and body weight, and appears to operate as a switch between the lean and obese states.
To investigate the relevance for humans, the researchers studied adipose tissue (fat) samples from lean and obese children and found that half of the overweight children showed the lowered expression of TRIM28 and the network of imprinted genes, paralleling the observations in mice.
Then they explored published data on identical twins who were discordant for obesity (i.e. one was lean and one was obese, despite their identical genetics) and again found similar trends to support existence of a similar epigenetic effect in humans.
This is the first finding of polyphenism in mammals; previously this phenomenon has been shown in insects such as bees (worker compared with Queen), ants and butterflies.
The work has important implications for our understanding of complex trait genetics, evolution, and medicine. The existence of an on-off switch is particularly intriguing in terms of therapeutic intervention for obesity and other epigenetically regulated disorders. For example, one could envisage targeting this epigenetic switch and thereby triggering a lifelong change in phenotype, from obese to lean.
The Gurdon Institute's Azim Surani, one of the paper's authors, commented:
"My lab discovered genomic 'imprinting' through curiosity-driven investigation of early mouse development nearly 30 years ago. Imprinting is conserved in humans, and is a key paradigm for epigenetic regulation of gene expression. Over the years, we and others have shown the critical role of imprinted genes in regulating mammalian development and physiology. This paper published today in Cell shows how basic research can lead to deep insights into human diseases such as obesity."
More information about the Surani lab.
Image reproduced from the paper under Creative Commons CC-BY license.