Krüppel‐like factor 6 participates in extravillous trophoblast cell differentiation and its expression is reduced in abnormally invasive placenta

Abstract

Trophoblast cell differentiation is of paramount importance for successful pregnancy. Krüppel‐like factor 6 (KLF6), a transcription factor with diverse roles in cell physiology and tumor biology, is required for trophoblast differentiation through the syncytial pathway. Herein, we demonstrate that extravillous trophoblast (EVT) cell migration and mesenchymal phenotype are increased upon KLF6 downregulation or the expression of a deletion mutant lacking its transcriptional regulatory domain (KΔac). Raman spectroscopy revealed molecular modifications compatible with increased differentiation in cells stably expressing the KΔac mutant. Moreover, abnormally invasive placenta showed lower KLF6 immunostaining compared with the normal placenta. Thus, impaired KLF6 expression or function stimulates EVT migration and differentiation in vitro and may contribute to the physiopathology of the abnormally invasive placenta.

A Multiomics, Spatiotemporal, and Single Cell Atlas for Mapping Cell-Type-Specific Dysregulation at the Maternal-Fetal Interface

“…Based on their cell-type-specific (correlated or anti- correlated) expression patterns and TF binding motif(s) in ATAC-seq peaks (± 250 bps of gene promoters), they mediated 167 high-confidence regulatory interactions (strength coefficient greater than 0.1) with 116 target genes (TGs). The GRN ( Fig.1G ) revealed several hub TFs mediating the most regulatory interactions, including ASCL2 and KLF6, known to regulate EVT differentiation(Miranda et al, 2022; Varberg et al, 2021), as well as ZNF704 and MBD2 (the NURD complex subunit) whose functions are not yet understood in this context. Notably, several genes whose expression were highly enriched in EVT were co-targeted by FOS, including the marker gene HLA-G (the best known EVT marker), KRT8 ( Fig.S9A ) and FN1 (fibronectin, Fig.S9B ).…”

“…The GRN (Fig. 1G) revealed several hub TFs mediating the most regulatory interactions, including ASCL2 and KLF6, known to regulate EVT differentiation (Miranda et al, 2022;Varberg et al, 2021), as well as ZNF704 and MBD2 (the NURD complex subunit) whose functions are not yet understood in this context. Notably, several genes whose expression were highly enriched in EVT were co-targeted by FOS, including the marker gene HLA-G (the best known EVT marker), KRT8 (Fig.…”