The Trithorax group protein dMLL3/4 instructs the assembly of the zygotic genome at fertilization

The transition from fertilized oocyte to totipotent embryo relies on maternal factors that are synthetized and accumulated during oocyte development. Yet, it is unclear how oocytes regulate the expression of maternal genes within the transcriptional program of oogenesis. Here, we report that the Drosophila Trithorax group protein dMLL3/4 (also known as Trr) is essential for the transition to embryo fate at fertilization. In the absence of dMLL3/4, oocytes develop normally but fail to initiate the embryo mitotic divisions after fertilization. This incapability results from defects in paternal genome reprogramming and maternal meiotic completion. The methyltransferase activity of dMLL3/4 is dispensable for both these processes. We further show that dMLL3/4 promotes the expression of a functionally coherent gene subset that is required for the initiation of post‐fertilization development. Accordingly, we identify the evolutionarily conserved IDGF4 glycoprotein (known as oviductin in mammals) as a new oocyte‐to‐embryo transition gene under direct dMLL3/4 transcriptional control. Based on these observations, we propose that dMLL3/4 plays an instructive role in the oocyte‐to‐embryo transition that is functionally uncoupled from the requirements of oogenesis. Synopsis The histone methyltransferase dMLL3/4 allows oocytes to acquire embryo fate at fertilization. dMLL3/4 promotes the expression of a coherent genetic program including a new oocyte‐to‐embryo transition gene, the IDGF4 glycoprotein. dMLL3/4 is dispensable for normal oocyte differentiation but essential for unpacking the sperm genome and the completion of female meiosis at fertilization. The methyltransferase activity of dMLL3/4 is not required for the oocyte‐to‐embryo transition. dMLL3/4 selectively promotes, during oogenesis, the expression of a small subset of genes that are fundamental for the acquisition of embryo fate. The IDGF4 glycoprotein (a direct target of dMLL3/4) regulates the initiation of the embryo mitotic divisions. Graphical Abstract The histone methyltransferase dMLL3/4 allows oocytes to acquire embryo fate at fertilization. dMLL3/4 promotes the expression of a coherent genetic program including a new oocyte‐to‐embryo transition gene, the IDGF4 glycoprotein.