Meta-signature of Human Endometrial Receptivity: A Meta-Analysis and Validation Study of Transcriptomic Biomarkers

Sci Rep. 2017 Aug 30;7(1):10077. doi: 10.1038/s41598-017-10098-3.

Abstract

Previous transcriptome studies of the human endometrium have revealed hundreds of simultaneously up- and down-regulated genes that are involved in endometrial receptivity. However, the overlap between the studies is relatively small, and we are still searching for potential diagnostic biomarkers. Here we perform a meta-analysis of endometrial-receptivity associated genes on 164 endometrial samples (76 from 'pre-receptive' and 88 from mid-secretory, 'receptive' phase endometria) using a robust rank aggregation (RRA) method, followed by enrichment analysis, and regulatory microRNA prediction. We identify a meta-signature of endometrial receptivity involving 57 mRNA genes as putative receptivity markers, where 39 of these we confirm experimentally using RNA-sequencing method in two separate datasets. The meta-signature genes highlight the importance of immune responses, the complement cascade pathway and the involvement of exosomes in mid-secretory endometrial functions. Bioinformatic prediction identifies 348 microRNAs that could regulate 30 endometrial-receptivity associated genes, and we confirm experimentally the decreased expression of 19 microRNAs with 11 corresponding up-regulated meta-signature genes in our validation experiments. The 57 identified meta-signature genes and involved pathways, together with their regulatory microRNAs could serve as promising and sought-after biomarkers of endometrial receptivity, fertility and infertility.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Computational Biology / methods
  • Embryo Implantation / genetics
  • Embryo Implantation / immunology
  • Endometrium / cytology
  • Endometrium / metabolism*
  • Exosomes / chemistry
  • Exosomes / metabolism
  • Female
  • Fertility / genetics*
  • Fertility / immunology
  • Gene Expression Profiling
  • Gene Ontology
  • Gene Regulatory Networks*
  • Humans
  • Immunity, Innate
  • Menstrual Cycle / genetics*
  • Menstrual Cycle / immunology
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • Molecular Sequence Annotation
  • RNA, Messenger / genetics*
  • RNA, Messenger / immunology
  • Sequence Analysis, RNA
  • Transcriptome*

Substances

  • Biomarkers
  • MicroRNAs
  • RNA, Messenger