Mammalian early embryogenesis is a fundamental question in biology. Recent studies have demonstrated that global remodeling of chromatin structure plays a critical role in acquiring and maintaining toti- or pluri-potency. Although their exact function remains elusive, endogenous transposable elements (TEs), remnants of ancient transposons, are associated with dynamic chromatin remodeling in early embryogenesis. Furthermore, although trophoblast stem cells (TSCs) play essential roles in supporting embryonic development, little is known about their chromatin structure. TEs plays an essential role in the acquirement of placenta in eutherians during evolution. Intriguingly, the specification of the trophoblast lineage occurs when traditional epigenetic marks reaches the lowest point, indicative of the existence of novel mechanisms. DNA methylation is a critical factor in the regulation of chromatin structures. A series of recent studies, including ours, have discovered a novel type of DNA methylation, N6- methyladenine (N6-mA), in metazoans. In general, N6-mA is expressed at very low levels in adult mammalian tissues and can be upregulated under environmental stress or in tumorigenesis. N6-mA levels are greatly elevated in early embryogenesis in various metazoans, including mammals. Interestingly, we and others also demonstrated the specific role of N6-mA in silencing TEs in mouse embryonic stem cells, brains and human tumor cells. Our most recent results demonstrated a surprising function of N6-mA in promoting dynamic chromatin structures in stem cells thereby promoting the stem cell fate (TSCs), via stabilizing DNA secondary structure at TEs. This proposal aims to further investigate this novel mechanism. The outcome of this proposal will pave the way to a new research direction in epigenetics and embryogenesis.
This proposal focuses on underlying mechanisms of mammalian embryonic development, the results of which will benefit the understanding of embryogenesis and human diseases caused by faulty development.