Integrative genomics of gene and metabolic regulation by estrogen receptors α and β, and their coregulators

The closely related transcription factors (TFs), estrogen receptors ER alpha and ER beta, regulate divergent gene expression programs and proliferative outcomes in breast cancer. Utilizing breast cancer cells with ER alpha, ER beta, or both receptors as a model system to define the basis for differing response specification by related TFs, we show that these TFs and their key coregulators, SRC3 and RIP140, generate overlapping as well as unique chromatin-binding and transcription-regulating modules. Cistrome and transcriptome analyses and the use of clustering algorithms delineated 11 clusters representing different chromatin-bound receptor and coregulator assemblies that could be functionally associated through enrichment analysis with distinct patterns of gene regulation and preferential coregulator usage, RIP140 with ER beta and SRC3 with ER alpha. The receptors modified each other's transcriptional effect, and ER beta countered the proliferative drive of ER alpha through several novel mechanisms associated with specific binding-site clusters. Our findings delineate distinct TF-coregulator assemblies that function as control nodes, specifying precise patterns of gene regulation, proliferation, and metabolism, as exemplified by two of the most important nuclear hormone receptors in human breast cancer.