GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility

摘要: Estrogen receptor (ESR1) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcription events that promote tumor growth. Differences enhancer occupancy ESR1 contribute diverse expression profiles clinical outcome observed cancer patients. GATA3 is an ESR1-cooperating factor mutated tumors; however, its genomic properties are not fully defined. In order investigate composition enhancers involved estrogen-induced potential role GATA3, we performed extensive ChIP-sequencing unstimulated cells following estrogen treatment. We find pivotal mediating accessibility at regions ESR1-mediated transcription. silencing resulted a global redistribution cofactors active histone marks prior stimulation. These changes altered ESR1-binding profile subsequently occurred estrogen, with exhibiting both loss gain affinity, implying GATA3-mediated binding. The redistributed correlated gene expression, suggestive functionality. Chromatin loops TFF locus involving ESR1-bound independently when was silenced, indicating present on chromatin, may serve as licensing for estrogen-ESR1-mediated interactions between cis-regulatory elements. Together, these experiments suggest directly impacts accessibility, potentially explain contribution mutant-GATA3 heterogeneity ESR1+ cancer.