UHRF1 shapes both the trophoblast invasion and decidual macrophage differentiation in early pregnancy

Abstract

Trophoblasts play critical roles in establishment and maintenance of a normal pregnancy. Their dysfunction in early pregnancy is closely related to pregnancy‐related diseases, including recurrent pregnancy loss (RPL). Epigenetic modifications dynamically change during pregnancy; however, the role of the epigenetic modifier UHRF1 in trophoblast regulation remains unknown. This is the first study to show that UHRF1 expression was localized in the cytoplasm of cytotrophoblasts, syncytiotrophoblasts, and villi columns, and decreased in the villi of patients with RPL. The invasion and cell viability in a UHRF1 knockdown trophoblast cell line were significantly decreased. In addition, the mRNA expression profiles of Swan71 cells were partially altered by UHRF1 knockdown. The altered immune‐related genes were screened out and the pro‐inflammatory TH1‐type chemokine/cytokines CXCL2 and IL‐1β were identified as the most promising targets of UHRF1 in the trophoblasts, which were significantly increased in the UHRF1 knockdown Swan71 cells, villi, and serum from patients with RPL. The macrophages treated with the supernatants of UHRF1 knockdown Swan71 cells were polarized to the M1 phenotype and secreted high levels of pro‐inflammatory cytokines, which might be driven by the activated MyD88/NF‐κB signaling pathway and mediated by the increased expression of CXCR2 and IL‐1R1 (CXCL2 and IL‐1β receptors, respectively). In addition, the supernatants of UHRF1 knockdown Swan71 cells showed stronger chemotaxis to macrophages than those from the controls. Our findings highlight the previously unknown roles of UHRF1 as one of the key regulators on the trophoblasts and their cross‐talk with local immune cells, and demonstrate a potential approach for RPL intervention.

Macrophage plasticity and function in cancer and pregnancy

“…There are pieces of evidence that DNA methyltransferases (DNMTs) have a specific effect on the formation of macrophage phenotypes. Ubiquitin-like protein containing plant homeodomain (PHD) and RING finger domain 1 (UHRF1) maintains the DNA methylation status by recruiting DNMT1 ( 80 ). A recent study found that decreased UHRF1 in trophoblasts promotes the expression of pro-inflammatory IL-1β, which recruits monocytes to decidua and shifts them into the M1 phenotype, further exacerbating RPL ( 80 ).…”

“…Ubiquitin-like protein containing plant homeodomain (PHD) and RING finger domain 1 (UHRF1) maintains the DNA methylation status by recruiting DNMT1 ( 80 ). A recent study found that decreased UHRF1 in trophoblasts promotes the expression of pro-inflammatory IL-1β, which recruits monocytes to decidua and shifts them into the M1 phenotype, further exacerbating RPL ( 80 ). In cancer, DNA methylation is critical for the suppression of the expression of tumor suppressor genes, whereas the loss of DNA methylation mediated by removal of methyl groups leads to the overexpression of oncogenes.…”

Mapping Decidualization Resistance in Former Severe Preeclampsia Patients at Multi-Omic Levels

“…Decidualized stroma 2 cells co-expressed markers of the pre-decidual and decidual states, EGR1 and CXCL2 (25,26), respectively. Decidualized stroma 3 cells were characterized by well-known decidualization markers such as IGFBP1 and TIMP3 (27), ATF3 (28), and transcription factors that are associated with late decidualization, including CSRNP1 (3).…”

Endometrial TGFβ signaling fosters early pregnancy development by remodeling the fetomaternal interface

“…UHRF1, which shapes M1 to M2 decidual macrophage differentiation in early pregnancy, is decreased in patients with recurrent pregnancy loss, resulting in increased cytokines such as CXCL2. This leads to the recruitment of monocytes and promotes the polarization to the M1 phenotype 85 …”