Circadian gene Rev-erb alpha influenced by sleep conduces to pregnancy by promoting endometrial decidualization via IL-6-PR-C/EBP beta axis

Background: Sleep disturbance can cause adverse pregnancy outcomes by changing circadian gene expression. The potential mechanisms remain unclear. Decidualization is critical for the establishment and maintenance of normal pregnancy, which can be regulated by circadian genes. Whether Rev-erb alpha, a critical circadian gene, affects early pregnancy outcome by regulating decidualization needs to be explored. Methods: QPCR, western blot and artificial decidualization mouse model were used to confirm the effect of sleep disturbance on Rev-erb alpha expression and decidualization. The regulatory mechanism of Rev-erb alpha on decidualization was assessed using QPCR, western blot, RNA-Seq, and Chip-PCR. Finally, sleep disturbance mouse model was used to investigate the effect of therapeutic methods targeting Rev-erb alpha and interleukin 6 (IL-6) on improving adverse pregnancy outcomes induced by sleep disturbance. Results: Dysregulation of circadian rhythm due to sleep disturbance displayed abnormal expression profile of circadian genes in uterine including decreased level of Rev-erb alpha, accompanied by defective decidualization. Rev-erb alpha could regulate decidualization by directly repressing IL-6, which reduced the expression of CCAAT/enhancer-binding protein beta (C/EBP beta) and its target insulin-like growth factor binding protein 1 (IGFBP1), the marker of decidualization, by inhibiting progesterone receptors (PR) expression. Moreover, deficient decidualization, higher abortion rate and lower implantation number were exhibited in the mouse models with sleep disturbance compared with those in normal mouse. Pharmacological activation of Rev-erb alpha or neutralization of IL-6 alleviated the adverse effect of sleep disturbance on pregnancy outcomes. Conclusions: Taken together, Rev-erb alpha regulated decidualization via IL-6-PR-C/EBP beta axis and might be a connector between sleep and pregnancy outcome. Therapies targeting Rev-erb alpha and IL-6 might help improving adverse pregnancy outcomes induced by sleep disturbance.