Characterizing glial cells missing transcription factor 1 (GCM1)'s role in regulating placental gene expression

During gestation, the human fetus is dependent on the placenta for oxygen and nutrient exchange, waste removal, and immunological protection. Glial Cells Missing Transcription Factor 1 (GCM1) is critical to placental development, particularly during syncytialization. This study aims to characterize GCM1 regulation of gene expression using a GCM1 knockdown in placental syncytiotrophoblasts.

GCM1 expression was silenced using siRNA (knockdown; KD), and RNA sequencing was performed to quantify changes in gene expression. Primary trophoblast cells were treated with GCM1 siRNA during spontaneous syncytialization. BeWo choriocarcinoma cells were exposed to four conditions across differing syncytialization states: (1) Forskolin (FSK) alone, (2) GCM1 KD alone, (3) FSK followed by GCM1 KD (FSK + GCM1 KD), and (4) GCM1 KD followed by FSK (GCM1 KD + FSK).

One gene, PGF was decreased in primary trophoblasts after GCM1 KD. In the BeWo GCM1 KD group, there were 29 differentially expressed genes (DEGs) (FDR <0.05, |log₂FC| > 1), including 12 upregulated and 17 downregulated genes. The FSK + GCM1 KD group exhibited 44 DEGs (11 upregulated, 33 downregulated). The GCM1 KD + FSK group showed the largest transcriptional response, with 1838 DEGs (1131 upregulated and 707 downregulated). Across treatment conditions, these genes were enriched for pathways related to cytokine-cytokine receptor interaction, PI3K-Akt signaling, focal adhesion, MAPK signaling, and ovarian steroidogenesis.

These findings enhance our understanding of how GCM1 regulates gene expression during syncytialization and placental development. Identifying key pathways may provide insights into placental dysfunction and pregnancy complications.