Increasing evidence has emerged to suggest that environmental exposure during the prenatal period can increase the risk to develop diseases later in life. Prenatal exposure to tobacco smoke was described as a risk factor for a multitude of different diseases in children, including lung diseases, obesity, and cancer. However, the data supporting the relationship between environment, epigenetics, and transgenerational inheritance is still lacking due to the difficulties in sample collection and tools to dissect the complex data. We studied genome-wide, environmentally induced epigenetic changes and their functional relevance for disease risks later in life within a longitudinal mother-child birth cohort. By integrated analysis of longitudinal whole genome bisulfite sequencing, ChIP-sequencing and RNA sequencing, we unraveled a genome-wide epigenetic stable reprogramming converging upon transcriptional enhancers.
We found a number of disease related pathways deregulated, among them, the Wnt signaling, which is involved in the airway inflammatory response to cigarette smoke in smoking mothers as well as their newborn children. An association between epigenetic reprogramming of genes within the Wnt signaling pathway already at time of birth and the development of impaired lung function later in children’s life can be shown. (Molecular systems biology, 2016, Cover Article, featured in Science)
In addition, we computationally identified a novel DNA modification involved in transgenerational epigenetic inheritance in C.elegans, and CG14906 (mettl4) as U2 snRNA m6A methyltransferase, which was previously reported as a DNA m6A methyltransferase. This study answered a long-lasting question regarding to the enzymatic activity of mettl4, and thus pave the way for further investigating the functions of mettl4 in different biological settings. (Cell, 2015; Cell Research, 2020; Cell Discovery, 2020; Nature Machine Intelligence, 2020)
Understanding how the environment impacts our epigenome and pass the information to next generations would have massive implications on how we could approach and solve current complex diseases dominated by the interaction between environment and (epi)genetic composition.