Asymmetric RBBP7 regulates the first cell fate decision of early mammalian embryos.

Asymmetric transcription of noncoding RNA LincGET is currently recognized as the earliest event regulating the first cell fate decision in mammalian embryogenesis. However, whether key protein factors modulate this process remains elusive. Here, we identify RBBP7 as the earliest protein factor regulating developmental cell fate in mammals. Loss of RBBP7 drives cells towards ICM lineage. In mouse late 2-cell embryos, unequal translation of Rbbp7 contributes to its asymmetric protein distribution, which subsequently induces inversed asymmetric histone acetylation H3K9ac by interaction with HDAC1, thereby promoting cell differentiation. Interestingly, RBBP7 and LincGET exhibit a consistent asymmetric tendency but direct different cell fates; depletion or overexpression of both Rbbp7 and LincGET restored the cell fate bias, suggesting a coordinated regulatory mechanism during initial lineage specification. In summary, our study reveals RBBP7 as a new protein factor and elucidates its role in the first cell fate decision.