Alternative splicing in normal and pathological human placentas is correlated to genetic variants

Abstract

Two major obstetric diseases, preeclampsia (PE), a pregnancy-induced endothelial dysfunction leading to hypertension and proteinuria, and intra-uterine growth-restriction (IUGR), a failure of the fetus to acquire its normal growth, are generally triggered by placental dysfunction. Many studies have evaluated gene expression deregulations in these diseases, but none has tackled systematically the role of alternative splicing. In the present study, we show that alternative splicing is an essential feature of placental diseases, affecting 1060 and 1409 genes in PE vs controls and IUGR vs controls, respectively, many of those involved in placental function. While in IUGR placentas, alternative splicing affects genes specifically related to pregnancy, in preeclamptic placentas, it impacts a mix of genes related to pregnancy and brain diseases. Also, alternative splicing variations can be detected at the individual level as sharp splicing differences between different placentas. We correlate these variations with genetic variants to define splicing Quantitative Trait Loci (sQTL) in the subset of the 48 genes the most strongly alternatively spliced in placental diseases. We show that alternative splicing is at least partly piloted by genetic variants located either in cis (52 QTL identified) or in trans (52 QTL identified). In particular, we found four chromosomal regions that impact the splicing of genes in the placenta. The present work provides a new vision of placental gene expression regulation that warrants further studies.

Effects of Nifedipine and Labetalol Combined with Magnesium Sulfate on Blood Pressure Control, Blood Coagulation Function, and Maternal and Infant Outcome in Patients with Pregnancy-Induced Hypertension

“…While the placenta is not affected by drugs, which can have a satisfactory effect on the perinatal final maternal and infant outcome [ 8 , 9 ]. Labetalol, as a first-line drug for reducing blood pressure in PIH, is mainly due to its mild effect on lowering blood pressure and does not affect placental blood flow, which will not lead to symptoms such as low blood pressure and rapid heart rate [ 10 , 11 ]. Therefore, the present study outlines the clinical effectiveness of nifedipine and magnesium sulfate combined with labetalol in PIH, to guide clinical decision making in the selection of a better treatment plan.…”

Urothelial Cancer Associated 1 (UCA1) and miR-193 Are Two Non-coding RNAs Involved in Trophoblast Fusion and Placental Diseases

“…Another direction for future work is the assessment of the specific effects of the short isoforms of UCA1 that appear to be specifically modified when fusion occur. To note, we have recently demonstrated that alternative splicing is a general feature of placental disease, affecting hundreds of genes ( Ruano et al, 2021 ). This could be achieved by lentiviral transformation of the cell lines, or even primary cultures with this short isoform.…”

Knockdown of Splicing Complex Protein PCBP2 Reduces Extravillous Trophoblast Differentiation Through Transcript Switching

“…Recently, Ruano et al (2021) published the first systematic analysis of alternative splicing in third trimester placentas by microarray comparing preeclamptic and intra uterine growth restricted (IUGR) placentas to healthy controls. In their study, genes differentially spliced in preeclamptic placentas were predominantly associated with extracellular matrix organization pathways, genes differentially spliced in IUGR placentas were associated with hypoxia and hormone metabolism, while preeclampsia and IUGR both were associated with exocytosis.…”