Endometrial Receptivity: A Revisit to Functional Genomics Studies on Human Endometrium and Creation of HGEx-ERdb

BACKGROUND Endometrium acquires structural and functional competence for embryo implantation only during the receptive phase of menstrual cycle in fertile women. Sizeable data are available to indicate that this ability is acquired by modulation in the expression of several genes/gene products. However, there exists little consensus on the identity, number of expressed/not-detected genes and their pattern of expression (up or down regulation). METHODS Literature search was carried out to retrieve the data on endometrial expression of genes/proteins in various conditions. Data were compiled to generate a comprehensive database, Human Gene Expression Endometrial Receptivity database (HGEx-ERdb). The database was used to identify the Receptivity Associated Genes (RAGs) which display the similar pattern of expression across different investigations. Transcript levels of select RAGs encoding cell adhesion proteins were compared between two human endometrial epithelial cell lines; RL95-2 and HEC-1-A by quantitative real time polymerase chain reaction (q-RT-PCR). Further select RAGs were investigated for their expression in pre-receptive (n = 4) and receptive phase (n = 4) human endometrial tissues by immunohistochemical studies. JAr spheroid attachment assays were carried out to assess the functional significance of two RAGs. RESULTS HGEx-ERdb (http://resource.ibab.ac.in/HGEx-ERdb/) helped identification of 179 RAGs, of which 151 genes were consistently expressed and upregulated and 28 consistently not-detected and downregulated in receptive phase as compared to pre-receptive phase. q-RT-PCR confirmed significantly higher (p<0.005) expression of Thrombospondin1 (THBS1), CD36 and Mucin 16 transcripts, in RL95-2 as compared to HEC-1-A. Further, the pretreatment with antibodies against CD36 and COMP led to a reduction in the percentage of JAr spheroids attached to RL95-2. Immunohistochemical studies demonstrated significantly higher (p<0.05) expression of endometrial THBS1, Cartilage Oligomeric Matrix Protein (COMP) and CD36 in the receptive phase as compared to pre-receptive phase human endometrial tissues. CONCLUSION HGEx-ERdb is a catalogue of 19,285 genes, reported for their expression in human endometrium. Further 179 genes were identified as the RAGs. Expression analysis of some RAGs validated the utility of approach employed in creation of HGEx-ERdb. Studies aimed towards defining the specific functions of RAGs and their potential networks may yield relevant information about the major 'nodes' which regulate endometrial receptivity.