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

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.