The inheritance of traits from parent to offspring is a universal characteristic of life on earth, and has fundamental consequences for its inner workings, and for evolution. Recent results in the field of epigenetics have resurrected the once-discredited possibility that the environment of parents could have an effect on the phenotype of their offspring. Inheritance of acquired characters (ie passage of environmental information from one generation to the next) is often called """"""""Lamarckian"""""""" inheritance, and demonstration of its existence would drastically alter how we think about evolution, and how human epidemiological studies are carried out. I have used a microarray approach to identify transgenerational effects of the paternal environment on offspring phenotype in mice, linking paternal low protein diet to cholesterol metabolism in offspring. Furthermore, we have shown that this information is carried in sperm. In this project I propose to systematically characterize the mechanism by which environmentally-directed traits are inherited in mice. We will carry out whole-genome analysis of epigenetic information carriers in sperm, thereby identifying diet-directed changes in the sperm epigenome. In addition, using an innovative approach based on in vitro fertilization, we will systematically identify epigenetic marks that persist after fertilization. These studies will have a revolutionary impact on fields ranging from evolution to epidemiology.

Public Health Relevance

Epigenetic inheritance, the inheritance of information beyond DNA sequence, has been proposed to carry information about the environment between generations. We have discovered in mice that the paternal diet can have a profound influence on offspring's metabolic state. In this grant we propose to thoroughly investigate the mechanisms underlying transgenerational control of metabolic state in mammals, with important implications for the epidemiology of common human diseases such as diabetes.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genomics, Computational Biology and Technology Study Section (GCAT)
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Moss, Stuart B
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Sharma, Upasna; Conine, Colin C; Shea, Jeremy M et al. (2016) Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351:391-6
Wang, Feng; Shin, JongDae; Shea, Jeremy M et al. (2016) Regulation of X-linked gene expression during early mouse development by Rlim. Elife 5:
Hainer, Sarah J; McCannell, Kurtis N; Yu, Jun et al. (2016) DNA methylation directs genomic localization of Mbd2 and Mbd3 in embryonic stem cells. Elife 5:
Chen, Poshen B; Chen, Hsiuyi V; Acharya, Diwash et al. (2015) R loops regulate promoter-proximal chromatin architecture and cellular differentiation. Nat Struct Mol Biol 22:999-1007
Hainer, Sarah J; Gu, Weifeng; Carone, Benjamin R et al. (2015) Suppression of pervasive noncoding transcription in embryonic stem cells by esBAF. Genes Dev 29:362-78
Rando, Oliver J; Simmons, Rebecca A (2015) I'm eating for two: parental dietary effects on offspring metabolism. Cell 161:93-105
Friedman, Nir; Rando, Oliver J (2015) Epigenomics and the structure of the living genome. Genome Res 25:1482-90
Shea, Jeremy M; Serra, Ryan W; Carone, Benjamin R et al. (2015) Genetic and Epigenetic Variation, but Not Diet, Shape the Sperm Methylome. Dev Cell 35:750-8
Yildirim, Ozlem; Hung, Jui-Hung; Cedeno, Ryan J et al. (2014) A system for genome-wide histone variant dynamics in ES cells reveals dynamic MacroH2A2 replacement at promoters. PLoS Genet 10:e1004515
Sharma, Upasna; Rando, Oliver J (2014) Father-son chats: inheriting stress through sperm RNA. Cell Metab 19:894-5

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