GEO series

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

GSE292302 Homo sapiens; Mus musculus Expression profiling by high throughput sequencing 42 samples Submitted 2026/05/17 Platform GPL28038Platform GPL28457

Summary

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.

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Direct links to NCBI, no account and no request form: the whole study as GSE292302_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 42 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1237849 and SRA study SRP571360. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Study design

15 conditions, mostly in triplicate

HT29_ETS2_AID_Ctrl ×3 HT29_ETS2_AID_IAA ×3 Myc_fl_fl_Lgr5_Cre_Vehicle ×3 Myc_fl_fl_Lgr5_Cre_TAM ×3 HT29_MYC_AID_Ctrl ×3 HT29_MYC_AID_IAA ×3 LoVo_MYC_AID_Ctrl ×3 LoVo_MYC_AID_IAA ×3 +7 more

Supports a between-group comparison across 40 samples.

15 replicated groups read from the first 40 of 42 sample titles; they account for 40 of them. Check it against the sample list below before relying on it.

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