Molecular mechanisms controlling intergenerational epigenetic inheritance in mammals

Sexual reproduction controls genetic variation, phenotypic variability, and fitness of offspring. In mammals, gametes of opposite sexes are often morphologically and functionally dimorphic. This includes parental differences in chromatin states which are essential for proper mammalian development. The extent of such regulation beyond classical paradigms such as genomic imprinting and imprinted X-inactivation, however, remains largely unknown. I will discuss our latest findings in characterizing mechanisms regulating intergenerational epigenetic heritability and controlling embryonic development.

We recently demonstrated the importance of controlling the target specificity of the de novo DNA methylation machinery in mouse oocytes, thereby defining their competence for embryonic development. Maternal transmission of aberrant hyper DNA methylation at regulatory CpG islands is detrimental to pre-implantation development. Our data indicates limited epigenetic reprogramming of methylated CGIs in early embryos and suggests high sensitivity of such embryos to gene dosage disturbances.

Our ongoing single molecule chromatin footprinting studies in mature mouse and human sperm further demonstrate low nucleosome occupancy at gene regulatory sequences. Our findings support a stochastic rather than programmed potential role of residual nucleosomes in mammalian sperm in regulating paternal gene expression during ensuing embryonic development.