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EndoTime: Non-categorical timing estimates for endometrial tissue during the secretory phase

ABSTRACT: It is estimated that 1% of women suffer from Recurrent Pregnancy Loss (RPL), a debilitating condition currently defined as three or more consecutive miscarriages with no known preventative treatment. However, as 65% of women are able to successfully bear children following diagnosis the risk of RPL appears to be relatively transient. The foundation for embryo implantation is the endometrium – a complex heterogenous tissue that is also transitory in nature, and which dynamically cycles between phases of proliferation, maintenance and elimination. In order to identify biomarkers for the prediction of pregnancy outcome, we generated RNA-seq libraries of 36 endometrial biopsies from women with a quantified pregnancy history. Each biopsy was timed relative to the pre-ovulatory luteinizing hormone surge to coincide with the midluteal implantation window (reported as LH+ for days following the surge), and later associated with the outcome of pregnancy: ‘live birth’, ‘miscarriage’ or ‘ongoing after 12 weeks’. This sample set was anticipated to represent mid-luteal tissues, but observed temporal signatures suggested that this assignment was incorrect. We developed EndoTime as a result of these findings, utilising RT-qPCR expression data for a panel of six temporal marker genes in order to estimate endometrial biopsy timing along a continuous domain.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180485 | GEO | 2021/12/04

REPOSITORIES: GEO

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Project description:Pregnancy loss is the most common complication of human pregnancy. Recurrent early pregnancy loss (REPL) has multiple etiologies, including endometrial dysregulation leading to “suboptimal” implantation. Although the implantation process is tightly regulated in Eutherian (placental) mammals, the molecular factors contributing to dysregulated endometrial gene expression patterns in women with REPL are largely unknown. We hypothesized that genes that gained novel expression in the endometria of mammals that evolved in the Eutherian stemlineage, coincident with the evolution of pregnancy, are likely essential for establishment and maintenance of normal pregnancy and are, therefore, good candidates for genes whose expression may be dysregulated in disorders such as REPL. To test this hypothesis, we took an evolutionary forward genomics approach to characterize gene expression profiles of midsecretory endometria from women with REPL associated with abnormal endometria based either on histology or molecular expression of cyclin E. We identified 58 genes that were differentially expressed (P<0.001) between women with out-of-phase histological dating vs normal histology, and 81 genes that were differentially expressed (P<0.001) between women with abnormally elevated cyclin E levels vs normal cyclin E. Remarkably, genes that were recruited into endometrial expression during the evolution of pregnancy in Eutherian mammals were significantly enriched for dysregulated genes (P=0.002 for histology, P=0.021 for cyclin E), as well as for immune and signaling pathways with essential roles in endometrial biology. Thus, our novel evolutionary-based forward genomics approach identified genes whose dysregulation during the mid-secretory phase likely contributes to the molecular etiologies of recurrent early pregnancy loss. Total RNA obtained from mid luteal phase endometrium (two replicates per biopsy) from women with recurrent early pregnancy loss (REPL). Endometrial gene expression levels were compared 1) between women with out-of-phase (n=10) and normal histological dating (n=22), 2) between women with abnormally elevated (n=9) and normal (n=23) cyclin E levels. For 5 additional women with abnormally high cyclin E levels, biopsy samples were collected before and after progesterone treatment to investigate the gene expression profiles in response to progesterone.

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EndoTime: Non-categorical timing estimates for endometrial tissue during the secretory phase

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