Stage-specific expression dynamics of ESRRG orchestrate zygotic genome activation in mouse embryos

The estrogen-related receptor (ERR) family, comprising ESRRA (estrogen-related receptor alpha), ESRRB (estrogen-related receptor beta), and ESRRG (estrogen-related receptor gamma), plays a crucial role in regulating metabolic and developmental processes. However, the functional significance of ERRs during preimplantation embryo development remains largely unclear. In the present study, we aimed to systematically characterized ERRs expression dynamics in mouse preimplantation embryo development and elucidated the mechanistic involvement of ERRs in blastocyst formation. Our findings demonstrate that among the estrogen-related receptor family, ESRRG is uniquely and highly expressed at the 2-cell embryo stage and is essential for blastocyst formation. Knockdown of Esrrg significantly reduced global transcriptional activity in the 2-cell embryos, thereby impairing zygotic genome activation (ZGA) and disrupting the 2-cell to 4-cell embryo transition. Given the crucial role of ESRRG in ZGA, the mechanisms governing its own transcriptional regulation are of paramount interest. To this end, we searched for upstream regulators and identified trichorhinophalangeal syndrome I (TRPS1) as a key transcription factor that directly binds to the Esrrg promoter to modulate its expression. Furthermore, the TRPS1-ESRRG regulatory axis orchestrates mouse preimplantation development by controlling the expression of critical ZGA factors, such as Sp1 transcription factor and tankyrase 2. These results establish the TRPS1-ESRRG axis as a critical regulator of mouse preimplantation development through its essential role in modulating zygotic genome activation.