Global DNA and protein interactomes of FLT1P1 (Fms-related tyrosine kinase 1 pseudogene 1) revealed its molecular regulatory functions associated with preeclampsia.

ABSTRACT

BACKGROUND: Preeclampsia (PE) is one of the most serious pregnancy complications with unknown pathogenesis. Emerging evidence has demonstrated that Fms-related tyrosine kinase 1 (FLT1) is highly involved in PE development. As a pseudogene of FLT1, FLT1P1 increased in PE samples. However, its functions remain largely unknown. METHODS AND RESULTS: In this study, co-expression analysis was performed to identify the potential target genes of FTL1P1. Then chromatin isolation using RNA purification (ChIRP) method was employed to explore the interactomes of FLT1P1, including interacting with DNA fragments and proteins. We found that in PE samples, both FLT1P1 and FLT1 were highly expressed and closely correlated. ChIRP-protein data revealed that FLT1P1 interacts with translation- and transcription-related proteins, including 4 transcription factors (TFs). ChIRP-DNA analysis revealed that FLT1P1 preferentially interacted with DNA fragments downstream of transcription start sites (TSSs). Functional analysis of its interacting genes revealed that they were enriched in transcriptional regulation and apoptosis-related pathways. Twenty-six TFs, including CREB1 and SRF, were extracted from the potential FLT1P1-interacting gene sets and were potential targets of FLT1P1. CREB1 could bind to FLT1 promoter, and was negatively correlated with FLT1 at the expression level, making it a potential regulator of FLT1. CONCLUSIONS: Our study extensively investigated the interactome profiles of FLT1P1, especially the prompter region of TF gene CREB1, and revealed the potential molecular regulatory mechanisms of FLT1 expression in PE samples. Our results provide a novel view of PE pathogenesis, and suggest that FLT1P1 could serve as a potential therapeutic target in PE diagnosis and treatment.