During programmed decidualization in rodents, uterine stromal cells undergo extensive cellular and molecular reprograming into morphologically and functionally distinct decidual cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. However, the underlying mechanism governing this spatiotemporal specificity of decidualization remains elusive. Here, we demonstrated that uterine deletion of Men1, a key component of the MLL1/2 histone methyltransferase complex, disrupted the terminal differentiation of stromal cells, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 distribution in chromatin recapitulates the enrichment of transcription active modification H3K4me3 orchestrating spatiotemporal decidualization of stromal cells. Further transcriptomic investigation demonstrates that Men1 directly regulated the expression of PTX3, an extra-cellular trap for FGF2, in a H3K4me3 dependent manner in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and stromal cell differentiation during decidualization. In brief, our study provides genetic evidence and molecular mechanism for epigenetic rewiring mediated decidual regionalization by Men1 and shed new light in pregnancy maintenance.