Eliopoulos, A. | bioRxiv Science

bioRxiv2025

Trithorax balances ISC fate decisions via Ptx1-mediated repression of EE specification

Adult stem cells must coordinate transcriptional programs with external cues to maintain tissue homeostasis. In the Drosophila midgut, intestinal stem cells (ISCs) generate enterocytes (ECs) or enteroendocrine (EE) cells through Notch-dependent fate decisions, but how chromatin regulators influence this balance remains unclear. In this study we identified the Trithorax gene (trx) as a key factor that safeguards ISC lineage fidelity. Trx depletion biases ISCs toward EE differentiation without affecting proliferation, a phenotype exacerbated during aging or DSS-induced damage. Transcriptomic and chromatin profiling revealed the homeobox transcription factor Ptx1 as a Trx-dependent target. Ptx1 knockdown phenocopies Trx loss, whereas Ptx1 overexpression reverts trx-RNAi-induced EE overproduction, establishing Ptx1 as a critical mediator of Trx function. These findings support a model in which Trx constrains the scute-prospero axis through Ptx1-mediated repression, thereby limiting inappropriate EE specification and maintaining ISC plasticity.

cell biology↗

bioRxiv2024

Invariant Natural Killer T cells control positively and negatively the development of hepatocellular carcinoma

The liver routinely encounters antigens from the gut, triggering pro- inflammatory responses. Unresolved inflammation can lead to liver damage, steatosis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCC is influenced by various immune cells, including invariant natural killer T (iNKT) cells, which exhibit both innate and adaptive immunity traits. Here, we examined iNKT cell dynamics in a diethyl-nitrosamine (DEN)-induced HCC mouse model. We observed a significant reduction in iNKT cell numbers in HCC livers due to apoptosis and impaired cytokine production. CD1d-deficient mice, which lack iNKT cells, displayed delayed tumor initiation and lower tumor and foci number. However, these tumors were larger in size and characterized by enhanced proliferation and immunosuppression. Interestingly, adoptive transfer of healthy iNKT cells post-tumor establishment reduced tumor burden, highlighting their potential therapeutic role. Our findings suggest that iNKT cells contribute to early HCC development, while in later stages they help to control tumor growth, thus underscoring their complex role in liver carcinogenesis. Further understanding of iNKT cell functions may inform novel immunotherapeutic strategies for HCC management.

immunology↗