Mammalian parental imprinting as an epigenetic paradigm

Parental imprinting is an epigenetic phenomenon in which genes are expressed exclusively from only one of the parental alleles in a mono-allelic fashion. This form of regulation is determined in the germ-line, where differential DNA methylation marks originating in the sperm and oocyte are maintained throughout fertilization, resulting in parent-specific Differentially Methylated Regions (DMRs). In this classic epigenetic paradigm, DNA methylation is essential for maintaining the monoallelic expression of imprinted genes. Furthermore, hypermethylation or demethylation of parent-specific DMRs result in gene dosage effects of the respective imprinted genes, in a highly predictive manner. Early work in the field demonstrated that proper maintenance of parent-specific methylation marks following fertilization is essential for normal development, and that stochastic loss-of-imprinting in somatic cells may contribute to tumor progression and disease phenotypes. These observations led to the prevailing hypothesis that parent-specific DNA methylation marks are passively maintained during development and in adult tissues, thus conforming to the overall static methylation landscape of somatic cells.

Yet our recent work has demonstrated the existence of striking dynamics in parent-specific methylation, resulting in highly reproducible tissue- and cell type-specific patterns in embryos, as well as in adult mice. Intriguingly, our study revealed methylation changes to be dynamic also in the adult brain, potentially contributing to cellular epigenetic heterogeneity over time, with implications for aging. Taken together, our findings challenge the current dogma, supporting a dynamic role of DNA methylation in regulating imprinted DMRs during development. We therefore hypothesize that modulating imprinted gene dosage, via epigenetic regulation, may play a major role in normal development.

Our lab research focuses on establishing in-vitro and transgenic mouse models to functionally dissect the relationship between DNA methylation changes and parent-of-origin gene regulation during early embryonic development, gametogenesis and in the adult. Another area of active research is studying the contribution of misregulation of DNA methylation at imprinted regions to disease and transformation.