In silico analysis of the Mus musculus uterine gene expression landscape during pregnancy identifies putative upstream regulators for labour.

BACKGROUND: The molecular pathways involved in the transition from uterine quiescence to overt labour are mapped and form the currently established pharmacological targets for both the induction and inhibition of human labour. However, both spontaneous premature labour and functional dystocia occur and are difficult to treat adequately. The identification of upstream regulators involved in the onset and orchestration of labour pathways is essential to develop additional therapies that will contribute to the regulation of the timing of birth.

OBJECTIVES: To define uterine biological processes and their upstream activators involved in the transition from uterine quiescence to overt labour.

STUDY DESIGN: The uterus of non-pregnant and pregnant FVB M. musculus is collected at embryonic days (E) 6.5, 8.5, 10.5, 12.5, 15.5 and 17.5 and the uterine transcriptome is determined using the Illumina mouse Ref8v2 micro-array platform. K-means clustering and Ingenuity Pathway Analysis are applied to further dissect the transcriptome data.

RESULTS: From E6.5 to E17.5, 5405 genes are significantly differentially expressed and they segregate into 7 unique clusters. Five of the 7 clusters are enriched for genes involved in specific biological processes that include regulation of gene-expression, T-cell receptor activation, Toll-like receptor signalling and steroid metabolism. The identification of upstream activators for differentially expressed genes between consecutive time points highlights the E10.5 to E12.5 window during which the role from progesterone switches from an activated state to the inhibited state reflecting the process of functional progesterone withdrawal essential for the transgression from myometrial quiescence to synchronized contractions. For this time window in which 189 genes are differentially expressed we define 22 putative upstream activators of which NUPR1 and TBX2 are the most significant with respectively an activated and an inhibited status.

CONCLUSIONS: Gene expression profiling of mice uterus from E6.5 to E17.5 results in 7 unique gene expression clusters from early to late pregnancy that define the landscape of molecular events in ongoing pregnancy. In the current dataset progesterone is predicted as an activated upstream regulator and maintainer of myometrial quiescence and is active till E10.5. Progesterone is predicted as an inhibited upstream regulator at E12.5. We identify 22 upstream regulators in the E10.5 to E12.5 time window where the switch to progesterone withdrawal occurs. They are putative relevant upstream activators of labour.