Recurrent pregnancy loss (RPL) is a distressing pregnancy disorder experienced by ~2.5% of women who try to conceive. Dysregulation of decidual function is an important factor leading to RPL, but the underlying genetic factors remain unknown. We discovered that the methyltransferase SETD1B and a non-coding circular RNA (circSTK40) were significantly down-regulated in the decidual tissue of RPL patients compared to those with healthy pregnancies. SETD1B knockdown resulted in increased apoptosis, decreased autophagy, and increased glycolysis, which could disrupt decidual function among those with RPL. Circstk40 overexpression upregulated SETD1B and alleviated apoptosis, lactic acid accumulation, and autophagy inhibition. Mechanistically, circSTK40 bound to both SETD1B and histone H3, promoting interactions between the two proteins and consequently increasing H3K4 methylation levels. H3K4me2 and H3K4me3 modifications in the SETD1B promoter enhanced transcription of this gene, forming a putative positive feedback loop between SETD1B and H3K4me2/H3K4me3. SETD1B and circSTK40 coordinately promoted decidua survival and function for pregnancy maintenance. Our findings reveal a novel molecular mechanism underlying RPL, providing valuable targets for future research into functional RPL treatments.
Zhou et al. (Sat,) studied this question.