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 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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Conine, Colin C; Sun, Fengyun; Song, Lina et al. (2018) Small RNAs Gained during Epididymal Transit of Sperm Are Essential for Embryonic Development in Mice. Dev Cell 46:470-480.e3
Chan, Io Long; Rando, Oliver J; Conine, Colin C (2018) Effects of Larval Density on Gene Regulation in Caenorhabditis elegans During Routine L1 Synchronization. G3 (Bethesda) 8:1787-1793
Sharma, Upasna; Sun, Fengyun; Conine, Colin C et al. (2018) Small RNAs Are Trafficked from the Epididymis to Developing Mammalian Sperm. Dev Cell 46:481-494.e6
Vallaster, Markus P; Kukreja, Shweta; Bing, Xin Y et al. (2017) Paternal nicotine exposure alters hepatic xenobiotic metabolism in offspring. Elife 6:
Sharma, Upasna; Rando, Oliver J (2017) Metabolic Inputs into the Epigenome. Cell Metab 25:544-558
Wang, Feng; McCannell, Kurtis N; BoŇ°kovi?, Ana et al. (2017) Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs. Cell Rep 21:3691-3699
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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:
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 351:391-396

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