Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Eutherian (placental) mammals exhibit great differences in the degree of placental invasion into the maternal endometrium, with humans being on the most invasive end. Previously, we have shown that these differences in invasiveness is largely controlled by the stromal fibroblasts of the maternal endometrium, with secondary effect on stroma of other tissues resulting in correlated differences in cancer malignancy. Here, we present a statistical investigation of the second dogma linking the phenotypic and transcriptional differences to the genomic changes across species, revealing the regulatory genomic sequence differences underlying these inter-species differences. We show that gain or loss of specific transcription factor binding site sequences are connected to the inter-species gene-expression differences in a statistically significant manner, with a particularly larger effect on stromal genes related to invasibility. We also uncover transcriptional factors differentially regulating genes related to pro- and anti- invasible property of stroma. This work extends the understanding of inter-species differences in stromal invasion to the causal genomic sequence differences paving new avenues to target stromal characteristics to regulate placental, or cancer invasion.