Chemical-induced chromatin remodeling reprograms mouse ESCs to totipotent-like stem cells

Totipotent cells have more robust developmental potency than any other cell types, giving rise to both embryonic and extraembryonic tissues. Stable totipotent cell cultures and deciphering the principles of totipotency regulation would be invaluable to understand cell plasticity and lineage segregation in early development. Our approach of remodeling the pericentromeric heterochromatin and re-establishing the totipotency-specific broad H3K4me3 domains promotes the pluri-to-totipotency transition. Our protocol establishes a closer match of mouse 2-cell (2C) embryos than any other 2C-like cells. These totipotent-like stem cells (TLSCs) are stable in culture and possess unique molecular features of the mouse 2C embryo. Functionally, TLSCs are competent for germline transmission and give rise to both embryonic and extraembryonic lineages at high frequency. Therefore, TLSCs represent a highly valuable cell type for studies of totipotency and embryology.

Automated summary

Totipotent cells have greater developmental potency compared to other cell types as they can give rise to both embryonic and extraembryonic tissues. Remodeling the pericentromeric heterochromatin and establishing the totipotency-specific broad H3K4me3 domains can promote the transition from pluripotency to totipotency. These stable totipotent-like stem cells (TLSCs) closely resemble mouse 2-cell (2C) embryos and possess unique molecular features. TLSCs are capable of germline transmission and can generate both embryonic and extraembryonic lineages at a high frequency.