CtBP restricts DUX-dependent and -independent genetic program for the 2-cell-like state in murine embryonic stem cells

Abstract

After fertilization, maternally deposited mRNA is cleared, and de novo mRNA is transcribed from the zygotic genome through zygotic genome activation (ZGA), a process known as maternal-to-zygotic transition (MZT) occurring in the mouse at 2-cell (2C) stage. 2C-like cells (2CLCs) marked by MERVL expression are transcriptionally similar to 2C embryos spontaneously emerge from mouse embryonic stem cells (mESCs). Although the emergence of 2CLCs completely depends on DUX function, a recent knockout study clearly showed that DUX is dispensable for mouse embryos, suggesting that DUX-independent molecular pathways are not recapitulated in 2CLCs. We present here that the disruption of C-terminal binding protein 1/2 (Ctbp1/2) activates DUX-dependent and -independent molecular pathway associated with the development of early mouse embryos mediated by the upregulation of Preferentially expressed antigen of melanoma family-like 7 (PRAMEL7). Furthermore, the abnormality of the gene expression profile caused by Dux KO is partially rescued by the overexpression of PRAMEL7 in mESCs. Our study provides new insights into the DUX-independent molecular pathway for the activation of early embryonic genes in mESCs.