Menin directs regionalized decidual transformation through epigenetically setting PTX3 to balance FGF and BMP signaling

Mengying Liu,Jinhua Lu,Wenbo Deng,Chuanhui Guo,Meng Liu,Shuangbo Kong,Haili Bao,Lu Tang,Changxian Zhang,Zhongxian Lu,Haibin Wang

doi:10.1038/s41467-022-28657-2

Abstract

During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. Here we show that uterine deletion of Men1, a member of the histone H3K4 methyltransferase complex, disrupts the terminal differentiation of stroma, resulting in chaotic decidualization and pregnancy failure. Genome-wide epigenetic profile reveals that Men1 binding in chromatin recapitulates H3K4me3 distribution. Further transcriptomic investigation demonstrates that Men1 directly regulates the expression of PTX3, an extra-cellular trap for FGF2 in decidual cells. Decreased Ptx3 upon Men1 ablation leads to aberrant activation of ERK1/2 in the SDZ due to the unrestrained FGF2 signal emanated from undifferentiated stromal cells, which blunt BMP2 induction and decidualization. In brief, our study provides genetic and molecular mechanisms for epigenetic rewiring mediated decidual regionalization by Men1 and sheds new light on pregnancy maintenance.

Highlights

During decidualization in rodents, uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively
We considered that the decrease of Ptx[3] caused by Men[1] deficiency contributed to excessive ERK1/2 activation induced by paracrine FGF2 produced by the layer of undifferentiated stromal cells
Associated transcription factors HOXA10, whose expression expanded throughout the PDZ and SDZ, have been reported to play an important role in establishing regionspecific decidual tissue during decidualization[7,45]

Summary

Introduction

Uterine stroma undergoes extensive reprograming into distinct cells, forming the discrete regions defined as the primary decidual zone (PDZ), the secondary decidual zone (SDZ) and the layer of undifferentiated stromal cells respectively. The fine-tuned interplay of these regionalization determinants synergistically or antagonistically promotes tissue homeostasis during decidualization How these genes are coordinated to specify the allocation of decidual cells remains largely unknown. We utilize a combination of genetic, biochemical, and pharmacological approaches to investigate the role of Men[1] in peri-implantation uteri and reveal that Men[1] ablation disrupts the appropriated differentiation of decidual stromal cells, resulting in unordered regionalization of decidualization and compromised pregnancy success. PTX3, an extracellular protein trapping FGF2, is identified as a Menin directly regulated downstream gene and provides insightful information for the orchestration of decidualization and pregnancy maintenance in curbing the cross-talk between FGF2-ERK1/2 and BMP2

Methods

Results

Conclusion