Hypomethylation of PRDM1 is associated with recurrent pregnancy loss.

Guizhen Du,Yun Fan,Xiumei Han,Shuyu Xu,Zhenyao Huang,Li Han,Yankai Xia,Qiaoqiao Xu,Ruohan Wang,Mingming Yu,Yan Zhang,Guangbo Fu,Xinru Wang,Chuncheng Lu,Shuyan Lv,Xiaomin Huang,Yufeng Qin

doi:10.1111/jcmm.15335

Abstract

Recurrent pregnancy loss (RPL) rates have continued to rise during the last few decades, yet the underlying mechanisms remain poorly understood. An emerging area of interest is the mediation of gene expression by DNA methylation during early pregnancy. Here, genome‐wide DNA methylation from placental villi was profiled in both RPL patients and controls. Subsequently, differentially expressed genes were analysed for changes in gene expression. Many significant differentially methylated regions (DMRs) were identified near genes dysregulated in RPL including PRDM1. Differentially expressed genes were enriched in immune response pathways indicating that abnormal immune regulation contributes to RPL. Integrated analysis of DNA methylome and transcriptome demonstrated that the expression level of PRDM1 is fine‐tuned by DNA methylation. Specifically, hypomethylation near the transcription start site of PRDM1 can recruit other transcription factors, like FOXA1 and GATA2, leading to up‐regulation of gene expression and resulting in changes to trophoblast cell apoptosis and migration. These phenotypic differences may be involved in RPL. Overall, our study provides new insights into PRDM1‐dependent regulatory effects during RPL and suggests both a mechanistic link between changes in PRDM1 expression, as well as a role for PRDM1 methylation as a potential biomarker for RPL diagnosis.

Highlights

The first two authors contributed to this study and they should be regarded as joint first authors
Despite numerous studies demonstrated that aberrant DNA methylation of genes is closely correlated with pregnancy loss, it remains unclear the roles of DNA methylome and transcriptome perturbations in Recurrent pregnancy loss (RPL) patients.[7]
We validated these binding sites by Chromatin immunoprecipitation (ChIP)-qPCR, and the results showed that FOXA1 and GATA2 significantly enriched in the hypo-methylated region near PRDM1 (Figure 2H)

Summary

| INTRODUCTION

Recurrent pregnancy loss (RPL), defined as more than two consecutive miscarriages, is viewed as a distinct disorder.[1] It is estimated that 5% of women experience two clinical miscarriages and approximately 1% experience three or more losses.[2] The aetiology of RPL is complicated, with known causal factors of RPL including genetic factors, anatomic abnormalities, autoimmune and endocrine factors.[3]. The aetiology of approximately half of RPL cases still remains unknown.[3–5]. The transitions from undifferentiated progenitors to differentiated trophoblast cells require dynamic epigenetic regulation,[6] suggesting a role for DNA methylation as a potential mechanism regulating trophoblast differentiation. Despite numerous studies demonstrated that aberrant DNA methylation of genes is closely correlated with pregnancy loss, it remains unclear the roles of DNA methylome and transcriptome perturbations in RPL patients.[7]. We aimed to investigate the DNA methylome and transcriptome perturbations in RPL patients

| MATERIALS AND METHODS

Findings

| DISCUSSION