Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss

Abstract

Abstract1-2% of all human pregnancies suffer from idiopathic recurrent pregnancy loss (RPL) and underlying molecular causes are poorly understood. Here we show that defective Protein Arginine Methyltransferase 1 (PRMT1) function in trophoblast progenitors is a molecular cause for early pregnancy failure. PRMT1 is conserved in trophoblast progenitors and conditional deletion of PRMT1 in mouse trophoblast progenitors arrests placenta and embryonic development leading to lethality [~]E7.5. Remarkably, a subset of idiopathic RPL is associated with loss of PRMT1 in cytotrophoblast progenitors (CTBs). Experiments with human trophoblast stem cells (hTSCs), derived from these RPL-patients as well as PRMT1-depleted hTSCs revealed that PRMT1 is crucial for trophoblast progenitors self-renewal. Employing RNA-seq and CUT&RUN-sequencing in hTSCs, CTBs and primary mouse trophoblast progenitors we discover that PRMT1 promotes transcription of trophoblast stem-state regulators, like TEAD4 and MYBL2, by directly enriching histone H4 arginine 3 asymmetric di-methylation (H4R3Me2a) at their chromatin loci. PRMT1 is also essential for extravillous trophoblast (EVT) development during human placentation, while loss of PRMT1 in hTSCs spontaneously promotes syncytiotrophoblast (STB) differentiation. Our findings indicate that PRMT1 is an epigenetic governor that orchestrates mammalian trophoblast development and implicate the therapeutic potential of targeting the PRMT1-H4R3Me2a axis to mitigate early pregnancy loss.