Alternative super-enhancers result in similar gene expression in different tissues

Abstract

Super-enhancers (SEs) are clusters of highly active enhancers, regulating cell type-specific and disease-related genes, including oncogenes1-3. The individual regulatory regions within SEs might be simultaneously bound by different transcription factors (TFs) and co-regulators such as P300, BRD4 and Mediator, which together establish a chromatin environment conducting to effective gene induction4-6. While cells with distinct TF profiles can have different functions, an unanswered question is how different cells control overlapping genetic programmes. Here, we show that the construction of oestrogen receptor alpha (ER)-driven SEs is tissue specific, and both the collaborating TFs and the active SE components are largely differing between human breast cancer-derived MCF-7 and endometrial cancer-derived Ishikawa cells; nonetheless, SEs common to both cell types have similar transcriptional outputs. In the MCF-7 cell line, ER-dominated SEs are also driven by the well-known FoxA1 and AP2{gamma} TFs, as described previously7, whereas in Ishikawa cells, FoxM1, TCF12 and TEAD4 are as important as ER for SE formation. Our results show that SEs can be constructed in several ways, but the overall activity of common SEs is the same between cells with a common master regulator. These findings may reshape our current understanding of how these regulatory units can fine-tune cell functions. From a broader perspective, we show that systems assembled from different components can perform similar tasks if a common functional trigger drives their assembly.