Navigating progestrone-driven gene regulatory networks in the mammary gland

The genome contains all the information required for organismal development and homeostasis, but gene expression must be tightly regulated in time and space. Enhancers (non-coding DNA elements) play a central role in this regulation by binding transcription factors and facilitating 3D chromatin interactions with target genes. This thesis explores how the steroid hormone progesterone, via its receptor (PR), controls gene expression through enhancer activity, with a focus on the mammary gland.
First, we developed new molecular tools to visualize PR signaling at the single-cell level and optimized conditions for robust detection. Next, we used these tools to perform a detailed analysis of the enhancer landscape of Wnt4, a key PR target gene in mammary tissue. We identified a shared 3D enhancer hub that consists of both PR as well as GRHL2 bound enhancers that regulates Wnt4 in both mouse and human mammary tissues via a two-step model. Furthermore, we identified Wnt4 enhancers in the mous kidney and lung and compared them to the enhancers identified in the mammary gland. We found that these enhancers were not conserved between tissues, sugessting tissue-specific regulation of Wnt4.