SETD7 methylates the endometrial master regulator HOXA10 to facilitate H3K4me1 peaking for endometrial decidualization

Abstract Epigenetic dysregulation in the human endometrium contributes significantly to infertility, and especially to recurrent implantation failure (RIF). Impaired endometrial decidualization is a major cause of RIF, although the underlying epigenetic mechanisms remain unclear. We found that among the H3K4 methyltransferases, only the mRNA of SET Domain Containing 7 (SETD7) was upregulated in the human endometrium during decidualization and that SETD7 was indispensable for the transition of human endometrial stromal cells from proliferation to decidualization. SETD7 deficiency reduced H3K4me1 peaks at the transcription start site (TSS) center of decidual signature genes while increasing H3K4me1 enrichment downstream of the TSS in cell cycle genes. Integrated transcriptomic and epigenomic analyses revealed that Homeobox A10 (HOXA10) cooperated with SETD7 to facilitate H3K4me1 distribution at decidual signature genes. In silico prediction and molecular assays indicated that SETD7 directly interacted with HOXA10 with high confidence and methylated HOXA10, most likely at lysine (K)392 within the homeodomain, thereby enhancing HOXA10 binding transcriptional activity and protein stability. Consistently, HOXA10 knockdown alone markedly suppressed H3K4me1 enrichment at the TSS center of the decidual marker IGFBP1, resulting in reduced decidual protein levels within HESCs. In mid-secretory endometrium from a subset of RIF patients, SETD7 and HOXA10 expression was decreased, whereas the cell proliferation marker MKI67 was elevated. Collectively, these findings demonstrate that SETD7 actively directs histone methylation at specific genomic regions through HOXA10 methylation, and highlight the potential of targeted epigenetic therapy for RIF.