Integrative Analysis Reveals Regulatory Programs in Endometriosis

Reprod Sci. 2015 Sep;22(9):1060-72. doi: 10.1177/1933719115592709. Epub 2015 Jun 30.

Abstract

Endometriosis is a common gynecological disease found in approximately 10% of reproductive-age women. Gene expression analysis has been performed to explore alterations in gene expression associated with endometriosis; however, the underlying transcription factors (TFs) governing such expression changes have not been investigated in a systematic way. In this study, we propose a method to integrate gene expression with TF binding data and protein-protein interactions to construct an integrated regulatory network (IRN) for endometriosis. The IRN has shown that the most regulated gene in endometriosis is RUNX1, which is targeted by 14 of 26 TFs also involved in endometriosis. Using 2 published cohorts, GSE7305 (Hover, n = 20) and GSE7307 (Roth, n = 36) from the Gene Expression Omnibus database, we identified a network of TFs, which bind to target genes that are differentially expressed in endometriosis. Enrichment analysis based on the hypergeometric distribution allowed us to predict the TFs involved in endometriosis (n = 40). This included known TFs such as androgen receptor (AR) and critical factors in the pathology of endometriosis, estrogen receptor α, and estrogen receptor β. We also identified several new ones from which we selected FOXA2 and TFAP2C, and their regulation was confirmed by quantitative real-time polymerase chain reaction and immunohistochemistry (IHC). Further, our analysis revealed that the function of AR and p53 in endometriosis is regulated by posttranscriptional changes and not by differential gene expression. Our integrative analysis provides new insights into the regulatory programs involved in endometriosis.

Keywords: ChIP-seq; endometriosis; gene expression; regulatory programs; transcription factor.

MeSH terms

  • Case-Control Studies
  • Chromatin Immunoprecipitation
  • Computational Biology
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Databases, Genetic
  • Endometriosis / genetics*
  • Endometriosis / metabolism
  • Endometriosis / pathology
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / genetics
  • Estrogen Receptor beta / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Gene Regulatory Networks*
  • Genetic Association Studies
  • Genetic Markers
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Humans
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • AR protein, human
  • Core Binding Factor Alpha 2 Subunit
  • ESR2 protein, human
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • FOXA2 protein, human
  • Genetic Markers
  • RUNX1 protein, human
  • Receptors, Androgen
  • TFAP2C protein, human
  • TP53 protein, human
  • Transcription Factor AP-2
  • Tumor Suppressor Protein p53
  • estrogen receptor alpha, human
  • Hepatocyte Nuclear Factor 3-beta