GSE169450
A TRIM66/DAX1/Dux axis suppresses the totipotent 2-cell-like state in murine embryonic stem cells
2 cell-like cells (2CLCs) resemble blastomeres of the 2-cell stage of embryo and are used as an in vitro model to understand the onset of zygotic genome activation (ZGA). 2CLCs comprise only ~1% of murine embryonic stem cells (mESCs). However, their specification remains unclear. Here, we show that TRIM66 restricts 2CLCs specification by repressing Dux in mESCs. Mutational assays and a solved crystal structure demonstrate that TRIM66's PHD finger recognizes H3K4K9me3 and Bromo domain recognizes H3K18ac. Moreover, TRIM66 functions as a bridge factor to recruit the transcriptional repressor Dax1 to the Dux promoter preventing expansion of 2CLCs in mESCs. Rrecruitment of Dax1 to the Dux promoter requires TRIM66 and TRIM66's repressive effect on Dux transcription is dependent on Dax1. Thus, beyond expanding the scope of known regulators of 2CLCs and showing TRIM66 as a chromatin-modification reader, our study suggests multiple strategies for harnessing the biotechnological and medical potential of 2CLCs. Overall design: Identifiy the transcriptome and histone modification changes in different mouse embryonic stem cells