Smoking kills almost 6 million people per year worldwide. The addictive component of tobacco, nicotine, represents a major cause of diseases such as cardiovascular injuries and cancer. There is strong indication that a genetic component exists underlying nicotine-related behaviors and dependence. However, changes in the genome as determined in twin studies or detection of single nucleotide polymorphisms (SNPs) explain only part of the human heritability of nicotine usage. Recent studies suggest that the proclivity t become nicotine dependent can be inherited from fathers and that changes in the environmental conditions of one generation affect and influence the health (or likelihood of acquiring disease states) of subsequent generations. In fact, information contained in the epigenome such as methylation patterns, nucleosome positioning, and small RNA populations, might be influenced by altering environmental conditions and can be transferred to the offspring during reproduction. Reviving Charles Darwin's and Jean-Baptiste Lamarck's idea that the inheritance of certain characteristics from one generation to the next can be influenced by changes in the environment, I have performed transcriptome analysis of offspring from nicotine-treated and control fathers, using microarray and RNA-seq to identify key genes whose expression levels change in progeny. The identified genes are involved in neurotransmitter release, neuropeptide signaling pathways and behavioral responses to nicotine. I hypothesize that in mouse progeny, changes in the expression levels of these genes are a consequence of epigenetic reprogramming resulting from exposure to nicotine in mouse fathers. I will investigate the gene expression profiles in different progeny groups and determine the effects of paternal exposure to nicotine on behavioral responses in offspring, eventually connecting the observed (epi)genotype with a phenotype. Furthermore, I will examine epigenetic regulatory mechanisms in sperm from nicotine- treated mice and controls performing in-vitro fertilization to exclude confounding effects such as mating preferences. Epigenome mapping studies, including RRBS, nucleosome retention mapping, and RNA- sequencing, in sperm from fathers will elucidate underlying mechanisms of transgenerational inheritance. The results of my study will contribute to a deeper understanding of how the epigenome regulates gene expression and how environmental factors can influence these mechanisms. This will lead to new approaches in prevention and treatment of nicotine dependence and diseases linked to chronic nicotine exposure and its transgenerational inheritance.
Tobacco use is the leading cause of preventable death worldwide. Addictive behaviors and changes in gene expression profiles caused by nicotine, the highly addictive component of tobacco, can be transferred to the next generation, influencing children's risk to become smokers themselves. The goal of the proposed work is to elucidate the mechanism by which paternal exposure to nicotine alters the epigenetic state in offspring. Understanding transgenerational control of nicotine-related behaviors is likely to lead to novel therapeutic targets for prevention of and intervention in epidemic nicotine dependence.
|Zhao-Shea, Rubing; DeGroot, Steven R; Liu, Liwang et al. (2015) Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal. Nat Commun 6:6770|
|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|