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Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis [PROX1 CUT&RUN Liver/MEF/Hep3B]

GSE284653 Homo sapiens; Mus musculus Genome binding/occupancy profiling by high throughput sequencing 22 samples Submitted 2024/12/18 Platform GPL21626Platform GPL21697
Summary
Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. While transcription master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternative fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and was sufficient to prevent liver tumorigenesis. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo and enabled the transition of hepatocellular carcinoma to cholangiocarcinoma. Conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide evidence for PROX1 as a hepatocyte-specific safeguard and support a model where cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage identity and thus prevent disease.
Published in
Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumorigenesis
Lim B, Kamal A, Gomez Ramos B et al. · Nature genetics 2025 · PMID 39948437 · doi:10.1038/s41588-025-02081-w
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Direct links to NCBI, no account and no request form: the whole study as GSE284653_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 22 samples. Raw sequencing reads are also available from ENA.

Also filed as BioProject PRJNA1199996 and SRA study SRP552484. Searching any of these in the dataset finder brings you back here.

Study design
6 conditions, mostly in triplicate
Liver Prox1 ×5 Liver IgG ×5 Hep3B Flag ×3 Hep3B IgG ×3 MEF Flag ×3 MEF IgG ×3

Supports a between-group comparison across 22 samples.

6 replicated groups read from 22 sample titles; they account for 22 of them. Check it against the sample list below before relying on it.

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