Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals

Benjamin R. Carone, Lucas Fauquier, Naomi Habib, Jeremy M. Shea, Caroline E. Hart, Ruowang Li, Christoph Bock, Chengjian Li, Hongcang Gu, Phillip D. Zamore, Alexander Meissner, Zhiping Weng, Hans A. Hofmann, Nir Friedman, Oliver J. Rando

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906 Scopus citations


Epigenetic information can be inherited through the mammalian germline and represents a plausible transgenerational carrier of environmental information. To test whether transgenerational inheritance of environmental information occurs in mammals, we carried out an expression profiling screen for genes in mice that responded to paternal diet. Offspring of males fed a low-protein diet exhibited elevated hepatic expression of many genes involved in lipid and cholesterol biosynthesis and decreased levels of cholesterol esters, relative to the offspring of males fed a control diet. Epigenomic profiling of offspring livers revealed numerous modest (∼20%) changes in cytosine methylation depending on paternal diet, including reproducible changes in methylation over a likely enhancer for the key lipid regulator Ppara. These results, in conjunction with recent human epidemiological data, indicate that parental diet can affect cholesterol and lipid metabolism in offspring and define a model system to study environmental reprogramming of the heritable epigenome.

Original languageAmerican English
Pages (from-to)1084-1096
Number of pages13
Issue number7
StatePublished - 23 Dec 2010

Bibliographical note

Funding Information:
We thank D. Haig for initial discussions motivating this experiment and K. Ahmad, P. Kaufman, C. Meiklejohn, Y. Nahmias, and members of the Rando lab for critical reading of the manuscript. O.J.R. is supported in part by a Career Award in Biomedical Sciences from the Burroughs Wellcome Fund, by grant GM088618 from NIGMS, and by the Mathers Foundation and is a member of the UMass Diabetes Endocrinology Research Center (DK32520). N.F. is supported by grants from the NIH and the US-Israel Binational Science Foundation (BSF). H.A.H. is supported by NSF, an Alfred P. Sloan Foundation Fellowship and a Dwight W. and Blanche Faye Reeder Centennial Fellowship in Systematic and Evolutionary Biology. P.D.Z. is supported by grants GM62862 and GM65236 from the NIGMS. N.H. is supported by the Meidan fellowship. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript.


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