Lightning Talk + Poster ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Identification of the WDR61 regulatory network on endometrial cell adhesion through chromatin immunoprecipitation sequencing (#414)

Wei Zhou 1 2 , Poppy Downing 1 2 , Madeleine Howe 1 2 , Michaela Sacco 1 2 , Leiani L Santos 1 2 , Ellen Menkhorst 1 2 , Wan Tinn Teh 1 3 4 5 , Tarana Lucky 3 6 , Evdokia Dimitriadis 1 2
  1. Department of Obstetrics, Gynaecology and Newborn Health, University of Melbourne, Melbourne, VIC, Australia
  2. Gynaecology Research Centre, Royal Women's Hospital, Melbourne, VIC, Australia
  3. The Royal Women’s Hospital, Parkville, VIC, Australia, Melbourne, Victoria, Australia
  4. Melbourne IVF, Melbourne, Victoria
  5. Epworth HealthCare, Melbourne, Victoria, Australia
  6. School of Medicine, Griffith University, Gold Coast, Queensland, Australia

Endometrial receptivity is facilitated by endometrial remodeling, which occurs within a narrow window in the mid-secretory phase. The onset of the receptive window in humans has recently been identified to be marked by a sudden activation of transcriptional factors that regulate gene expression in the endometrial epithelial cells. When the change of transcriptomic processes is dysregulated, implantation cannot occur. This is a potential root cause of dysregulated endometrial receptivity. WD-repeat-containing protein-61 (WDR61) is one such transcriptional regulator that we recently showed increases only when reaching the mid-secretory phase. This study aimed to identify the full regulatory network of WDR61 in endometrial epithelial cells, which remains unknown in any cell type. To confirm the regulation of WDR61 on cell adhesion, primary human endometrial epithelial cells were subjected to trophoblast progenitor spheroid (blastocyst surrogate) adhesion assay. Chromatin immunoprecipitation sequencing (ChiP-seq) was performed on Ishikawa cells (a receptive endometrial epithelial cell line) to determine the full spectrum of regulation on gene transcription. We identified that adhesion of trophoblast spheroids was impaired with siRNA knockdown of WDR61 in primary endometrial epithelial cells. In Ishikawa cells, ChiP-seq demonstrated 2,022 genes directly targeted by WDR61. Pathway analysis revealed enriched functions including focal adhesion, intracellular signaling and epithelial-mesenchymal transition. We further identified enriched binding of WDR61 to key receptivity gene families, including HOX family genes, canonical and non-canonical WNT genes, and genes related to PI3K signaling. This study identified the precise genes that are likely responsible for the rapid transition in epithelial cells to open the implantation window. In conclusion, our data provide the first evidence that WDR61 enhances endometrial epithelial cell adhesion and is likely a master regulator of the rapid transcriptional activity that needs to occur to reach receptivity and ensure embryo adhesion and implantation success.