Researchers at the University of Kansas Medical Center have identified a molecular gatekeeper essential for the earliest stages of pregnancy, an epigenetic enzyme called PRMT1 that governs the self-renewal and differentiation of trophoblast cells, the precursors of the placenta.
The study, published in Nature Communications by Purbasa Dasgupta, Soumen Paul, and colleagues, shows that PRMT1 (protein arginine methyltransferase 1) is required for trophoblast stem cells to maintain their identity and proliferate. When PRMT1 is lost, mouse embryos die around embryonic day 7.0, before the placenta can form. And in a subset of human patients with recurrent pregnancy loss (RPL), PRMT1 expression is significantly reduced.
The mechanism
PRMT1 catalyzes a specific epigenetic mark, asymmetric dimethylation of arginine 3 on histone H4 (H4R3Me2a), at the chromatin of key trophoblast stem-state regulator genes, including TEAD4 and MYBL2. This mark promotes RNA Polymerase II recruitment, activating transcription of these genes and maintaining the trophoblast stem cell state.
Through CUT&RUN sequencing, the team identified 1,547 PRMT1 target genes in human trophoblast stem cells (hTSCs), with TEAD and STAT motifs significantly enriched at PRMT1-bound regions.
When PRMT1 was knocked down in hTSCs (by approximately 80% via RNAi, complete knockout was not possible because the protein is essential for cell survival), the cells showed severely impaired proliferation, defective organoid formation, and a failure to differentiate into extravillous trophoblasts (EVTs), the cells that invade the maternal decidua to establish blood supply. Instead, the cells prematurely differentiated into syncytiotrophoblasts, the multi-nucleated cells that produce human chorionic gonadotropin (hCG).
Evidence from mouse models
Global PRMT1 knockout mice (Prmt1^Tm1a allele) died by approximately E7.0 with a smaller placenta primordium and a drastic loss of ESRRB-positive trophoblast stem/progenitor cells. Conditional knockout using the Eomes^CreER system to delete PRMT1 at E5.5 produced a similar phenotype: a reduced extraembryonic ectoderm region, a diminished trophoblast stem/progenitor population, and predominantly trophoblast giant cells remaining. Ex vivo cultures confirmed that PRMT1 deletion impairs trophoblast stem/progenitor cell expansion and reduces Tead4 expression.
Human pregnancy loss link
Placentae from patients with idiopathic recurrent pregnancy loss, which affects 1–2% of all implantation-confirmed pregnancies, showed significant downregulation of PRMT1, TEAD4, and MYBL2 expression by RNA-seq (n=4 placentae, including three first-trimester and one early second-trimester). Immunostaining confirmed reduced PRMT1 protein in cytotrophoblasts and EVT precursors of RPL placentae (p<0.01).
Patient-derived hTSC lines with low PRMT1 expression (PRMT1^LOW RPL-hTSCs) showed defective proliferation, impaired organoid formation, and defective EVT development. Strikingly, ectopic expression of PRMT1 in these patient-derived cells significantly restored proliferation, EVT differentiation, and TEAD4/MYBL2 mRNA expression, a proof of principle that the pathway is potentially targetable.
Limitations
The study includes several important caveats. The human RPL cohort is small (n=4 placentae), limiting generalizability. Complete PRMT1 knockout could not be achieved in hTSCs, the protein is essential for survival, so the team relied on RNAi-mediated knockdown. The proportion of idiopathic RPL cases attributable to PRMT1 defects remains unknown. And the therapeutic potential of targeting the PRMT1-H4R3Me2a axis, discussed in the paper as a future direction, was not tested.
Nevertheless, the identification of PRMT1 as a master epigenetic regulator of trophoblast development opens a new molecular window into a condition that has long been poorly understood at the mechanistic level.
Funding: NIH grants (HD113673, HD103161, HD062546, HD101319, HD119510), Burroughs Wellcome Fund Next Gen Pregnancy Initiative, and German Research Foundation (DFG).
Sources:
1. Dasgupta P, Kumar R, Ray S, Roy N, Niloy AJ, Vallakati M, Marsh C, Arnold SJ, Paul S. “Arginine methyltransferase PRMT1 equipoises trophoblast development to prevent early pregnancy loss.” Nature Communications. 2026. DOI: 10.1038/s41467-026-75452-4