41 Arginine methyl transferase and epigenetic equilibrium in trophoblast development to prevent early pregnancy loss

Abstract Abstract: Introduction Recurrent pregnancy loss (RPL), the failure of 2+ clinically relevant pregnancies, is experienced by ∼2.5% of women. The molecular pathogenesis of early trophoblast progenitor cells and their differentiation in RPL is poorly understood. Protein Arginine Methylation (PRMT1) is a major epigenetic modifier in mammalian placenta. Defective PRMT1 is associated with pathological complications, as it dictates the equilibrium of trophoblast stem cells and other lineages of trophoblast, extravillous trophoblast stem cells (EVT) and Syncytiotrophoblasts (ST). Our main aim is to understand the role of PRMT1 in balancing cell fate choices of TSCs and other trophoblast cells in early pathological pregnancies. We investigate how PRMT1 contributes to defective trophoblast progenitor development, and we seek to dissect the conserved transcriptional programming in mammalian placentation. Methods Discarded de-identified 1st trimester placentas from elective terminations and from patients with idiopathic RPLs were obtained with patient consent. We procured Prmt1 tm1a(EUCOMM)Wtsi mice that harbor the knock-out first (tm1a) allele (via Knockout Mouse Project). We also generated Prmt1 conditional ready mice by crossing Prmt1tm1a mice with mice ubiquitously expressing Flp recombinase. Results Idiopathic RPLs placentas are associated with reduction of PRMT1 expression in trophoblast progenitor populations. Using genetic mice and human trophoblast stem cells (hTSC), we provide evidence that a conserved PRMT1 is essential to maintain trophoblast progenitors and progression of pregnancy. Our mechanistic analysis provides evidence that PRMT1 regulates transcription of key genes by modifying histone arginine 4 methylation and their chromatin loci. Conclusions Depletion of PRMT1 in human TSCs impairs self-renewal and activates ST transcriptional programs. Impaired PRMT1 expression in RPL and hTSC is associated with the loss of TEAD4, a hippo pathway component. PRMT1 abrogation leads to loss of trophoblast progenitors in E7.5 mouse embryo. PRMT1 acts as gatekeeper of trophoblast stem cell propensity to differentiate.