Research

Epigenetic inheritance, the inheritance of phenotypic changes in the absence of changes in DNA, is essential for the transmission of cell states through cell division. In addition to epigenetic inheritance of cell states during organismal development, there is a growing body of evidence that epigenetic information can be transmitted from one generation to the next, with famous examples including RNA interference in C. elegans and paramutation in maize. Studies of cell-state and transgenerational epigenetic inheritance have identified chromatin structure, DNA modifications, small RNAs, and prions as major molecular carriers of epigenetic information. However, how epigenetic information is established during gametogenesis and how epigenetic marks affect offspring development remain deeply mysterious.

A significant implication of epigenetic inheritance via gametes is that, because epigenetic modifications are often regulated by environmental conditions, the environment experienced by parents may influence the phenotype of offspring via alterations to the gamete “epigenome”. Indeed, epidemiological studies of human populations suggest that parental diet can influence metabolic phenotypes in offspring, and even grandoffspring. Moreover, multiple studies in rodents have linked parental treatment regimes such as dietary alteration and intermittent stress with changes in offspring phenotype. Despite this wealth of evidence that paternal environment can influence offspring phenotype, we currently lack any mechanistic understanding of how dietary or other environmental information is transmitted to the next generation. Understanding the mechanism of intergenerational inheritance has important implications for public health and policy. Many common metabolic diseases, such as diabetes, have both genetic components and contributions from a patient’s lifestyle and environment. Only a fraction of the heritability of such diseases can be explained by genetic variation; instead, it is now increasingly appreciated that epigenetic inheritance likely contributes to such diseases.

Our lab is interested in understanding the mechanism of intergenerational epigenetic inheritance by elucidating key steps of the process: 1) how informational signals are generated in gametes, 2) how those signals are influenced by environment, and 3) how those signals influence offspring gene expression and development. Our previous work uncovered a role of sperm small RNAs in the intergenerational inheritance of paternal dietary effects (Sharma et al., Science, 2016). Our current research is focussed on examining the biogenesis and function of sperm small RNAs using a combination of genomic, molecular, and reproductive approaches.