# Tcl1 coordinately promotes metabolic shift and regulates totipotency exit

## TL;DR

This study shows how Tcl1 regulates the transition from totipotency to pluripotency by influencing energy metabolism and gene expression.

## Contribution

The novel contribution is identifying the Tcl1–AKT–succinate axis as a key regulator of the totipotency–pluripotency transition through metabolic control.

## Key findings

- Tcl1 absence upregulates totipotency genes and reduces H3K4me3 at glycolysis enzyme promoters.
- Reduced AKT activity is linked to 2C gene activation and altered energy metabolism.
- AKT inhibition causes succinate accumulation, linking it to cell fate transitions.

## Abstract

During early embryonic development, particularly in the transition from totipotency to pluripotency, energy metabolism is closely linked to cell fate. However, the essential regulators of energy metabolism in this transition remain unclear. In this study, we reveal that Tcl1 influences energy metabolic characteristics and regulates the totipotency–pluripotency transition. Our findings demonstrate that the absence of Tcl1 triggers the upregulation of totipotency genes and reduces H3K4me3 modifications at glycolysis enzyme promoters, thereby suppressing glycolytic processes. Furthermore, we found that a reduction in AKT, a downstream target of Tcl1, is associated with activation of the 2C gene and consequent shifts in energy metabolism. Specifically, AKT inhibition leads to succinate accumulation, further highlighting the role of succinate in the cell fate transition. Our findings underscore the central role of Tcl1–AKT–succinate axis in regulating totipotency and pluripotency through coordinated energy metabolic pathways.