A core transcriptional regulatory circuitry controls super-enhancer-driven activation of LGR5 in colorectal cancer: ChIP-seq

The core transcriptional regulatory program governed by a small set of master transcription factors is pivotal for establishing context-specific cellular features, as has been elegantly illustrated in embryonic stem cells. Here, we reported an uncharted role of master transcription factor MYC in actively regulating cancer-type specific super-enhancer (SE) activity, and identified a core transcriptional regulatory circuitry consisting of MYC, ETS2, and FOXP1 in colorectal cancer (CRC). MYC/ETS2/FOXP1 bound to their own SEs and the SEs of other circuitry factors, thereby rapidly amplifying transcriptional effects upon activation. The majority of SEs were co-occupied by all three circuitry factors, and acute perturbation of the circuitry factors severely and selectively repressed a series of SE-controlled genes. Furthermore, there was functional inter-dependency between the circuitry and BRD4 in regulating SE-driven transcription, and targeting the circuitry factors sensitized CRC cells to BET inhibition. Notably, the key stemness gene LGR5 was activated by a circuitry-controlled distal SE in CRC, which was one of the most significantly gained tumor-specific SEs and was required for establishing CRC liver metastases. Lgr5 transcription in intestinal stem cells (ISCs) was likewise sustained by a Myc-regulated SE. Depletion of Myc in murine ISCs led to shrink of Lgr5-positive cell population, and impaired the renewal capacity of ISCs and intestinal epithelium integrity. Collectively, our study unveiled a core transcriptional regulatory module in CRC, advanced current understanding of MYC in transcription regulation, and provided mechanistic explanation for LGR5 overexpression in cancer. These findings may pave the way for precisely targeting detrimental transcription events in CRC therapy.