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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD080224-05
Application #
9445322
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Moss, Stuart B
Project Start
2014-04-14
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
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
Chou, Hsin-Jung; Donnard, Elisa; Gustafsson, H Tobias et al. (2017) Transcriptome-wide Analysis of Roles for tRNA Modifications in Translational Regulation. Mol Cell 68:978-992.e4
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

Showing the most recent 10 out of 19 publications