TRPS1 modulates chromatin accessibility to regulate estrogen receptor alpha (ER) binding and ER target gene expression in luminal breast cancer cells

Common genetic variants in the repressive GATA-family transcription factor (TF) TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over 80 percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes estrogen receptor alpha (ER) to redistribute in the genome. ER redistribution leads to both repression and activation of dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the genomic distribution of ER, both activating and repressing transcription of genes related to cancer cell fitness. Breast cancer is the most common cancer among women. The majority of cases are luminal, which tend to be estrogen receptor alpha (ER)-positive. ER is well-studied among transcription factors (TFs) because it is ligand-activated. This allows for the rapid induction of ER activity and the identification of primary estrogen-responsive genes. Most TFs have not been so extensively characterized, because their activity is not so rapidly perturbable. TRPS1 is an atypical GATA family TF that is associated with corepressor complexes and transcriptional repression. Here, we use an inducible degron tag system to rapidly deplete endogenously-tagged TRPS1 in luminal breast cancer cells within 30 minutes. We find that TRPS1 directly decreases local chromatin accessibility. This decreases ER binding intensity at TRPS1-proximal ER binding sites. As an indirect effect, ER binding intensity distal to TRPS1 increases in intensity. These effects on ER binding are associated with changes in ER target gene transcription, repressing or activating these genes in concordance with the effect on ER binding intensity. Our work is consistent with a model in which TFs either exclusively activate or exclusively repress transcription of their direct target genes, with indirect primary response genes changing due to the redistribution of limiting activating TFs or coactivators.