Targeting the PRMT5/Nur77 methylation axis enhances endometrial decidualization capacity and female fertility in preclinical models
Zhiwen Cao, Xinyu Cai, Jie Mei, Na Kong, Yang Liu, Xiaoyue Shen, Min Wu, Xin Zhen, Jianxin Sun, Rong Li, Ruiwei Jiang, Haixiang Sun, Guijun Yan
Zhiwen Cao, Xinyu Cai, Jie Mei, Na Kong, Yang Liu, Xiaoyue Shen, Min Wu, Xin Zhen, Jianxin Sun, Rong Li, Ruiwei Jiang, Haixiang Sun, Guijun Yan
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Research Article Genetics Reproductive biology

Targeting the PRMT5/Nur77 methylation axis enhances endometrial decidualization capacity and female fertility in preclinical models

Abstract

Defective endometrial decidualization is one major cause of female infertility, yet the underlying mechanisms remain elusive. Here, we identified that protein arginine methyltransferase 5 (PRMT5), which was upregulated during decidualization and by progesterone stimulation, was markedly downregulated in the endometria of patients with recurrent implantation failure (RIF), along with a global reduction of symmetric dimethylarginine (SDMA). Uterine stroma-specific ablation of Prmt5 in mice severely impaired decidualization, leading to infertility. A multiomics analysis in human endometrial stromal cells (EnSCs) revealed that PRMT5 promoted decidualization primarily by catalyzing SDMA at arginine 346 (R346) of the orphan nuclear receptor Nur77, which directs its proper chromatin occupancy. Targeting the PRMT5/Nur77 methylation axis, we designed a peptide, Pep-Nur77R346K, which rescued the decidualization of multiple preclinical models: PRMT5-deficient human EnSCs, both genetic knockout (Prmt5d/d) and pharmacologically inhibited mouse models, and most importantly, primary RIF EnSCs. In a retrospective cohort of 114 participants, the correlated reductions of endometrial PRMT5/Nur77-R346me2s were confirmed, which demonstrated robust predictive value for pregnancy outcome. Our work establishes the PRMT5/Nur77 methylation axis as a key regulator of endometrial receptivity and highlights both a diagnostic biomarker and a peptide-based therapeutic potential for infertility.

Authors

Zhiwen Cao, Xinyu Cai, Jie Mei, Na Kong, Yang Liu, Xiaoyue Shen, Min Wu, Xin Zhen, Jianxin Sun, Rong Li, Ruiwei Jiang, Haixiang Sun, Guijun Yan

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Figure 4

PRMT5 methylates Nur77 and regulates its chromatin occupancy during decidualization.

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PRMT5 methylates Nur77 and regulates its chromatin occupancy during deci...
(A) Schematic of multiomics strategy to identify PRMT5 downstream effectors in human EnSCs, combining anti-PRMT5 IP-MS and pan-SDMA methylation proteomics. (B) Venn diagram showing overlap between SDMA-methylated proteins downregulated upon PRMT5 deficiency (knockdown/inhibition) and those deficient in RIF patient endometria. Intersection of PRMT5-interacting proteins (IP-MS) (C) with the 110 targets from B identifies Nur77 and FAM120A as core candidates (D). n = 1 pooled one sample per group. (E) Immunoprecipitation validation of overexpressed PRMT5-Nur77 interaction in HEK293T cells. (F) Immunoprecipitation analysis of endogenous PRMT5 and Nur77 protein levels and interaction following decidualization induction in EnSCs. (G) Western blot analysis of SDMA modification of Nur77 and total Nur77 protein levels upon PRMT5 knockdown. (H) Heatmap of Nur77 CUT&Tag peak intensity and signals specifically around the transcription start site (TSS) regions in control and PRMT5-knockdown EnSCs under decidualization. (I) Representative genome browser tracks of Nur77 occupancy, monomethylation of histone H3 at lysine 4 (H3K4me1), and input at the IGFBP1 and MAOA (monoamine oxidase A, a mitochondrial enzyme) loci. (J) Functional enrichment analysis of differentially expressed genes (DEGs) associated with lost or gained Nur77 peaks upon PRMT5 knockdown. (K) Motif analysis at Nur77-bound regions gained or lost after PRMT5 knockdown, respectively. OFP, orange fluorescent protein.