Experimental and Phylogenetic Evidence for Correlated Gene Expression Evolution between Dermal and Endometrial Fibroblasts: implications for the evolution of cancer malignancy

Abstract

Changes in transcriptional gene expression is a dominant mode of evolution, mostly driven by mutations at cis-regulatory regions. Mutations can affect gene expression in multiple cell types if the same cis-regulatory elements are used by different cell types. As a consequence, changes in gene expression in one cell type may be associated with similar gene expression changes in another cell type. Correlated gene expression change can explain correlated character evolution, as for instance the correlation between placental invasion and vulnerability to cancer malignancy. Here we test this hypothesis using a comparative and an experimental data set. Specifically, we investigate gene expression in dermal skin fibroblasts (SF) and uterine endometrial stomal fibroblasts (ESF). The comparative dataset consists of transcriptomes from cultured SF and ESF from 9 mammalian species. We calculated the independent phylogenetic contrasts (PIC) for each gene and cell type. We find that evolutionary changes in gene expression in SF and ESF are highly correlated, supporting the hypothesis that the correlated gene expression changes are a prevalent feature of gene expression evolution. The experimental data set derives from a SCID mouse strain that was selected for slow cancer growth which led to substantial changes in the SF compared to wild type SCID mice. We isolated SF and ESF from wild type and evolved SCID mice and compared their gene expression profiles. We find a significant correlation between the gene expression contrasts of SF and ESF, which supports the hypothesis that gene expression variation in SF and ESF is correlated. We discuss the implications of these findings for the hypothesized correlation between placental invasiveness and vulnerability to metastatic cancer.