Polycomb-mediated silencing of miR-8 is required for maintenance of intestinal stemness in Drosophila melanogaster

Zoe Veneti (), Virginia Fasoulaki, Nikolaos Kalavros, Ioannis S. Vlachos, Christos Delidakis and Aristides G. Eliopoulos ()
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Zoe Veneti: Foundation of Research & Technology Hellas
Virginia Fasoulaki: Foundation of Research & Technology Hellas
Nikolaos Kalavros: Beth Israel Deaconess Medical Center
Ioannis S. Vlachos: Beth Israel Deaconess Medical Center
Christos Delidakis: Foundation of Research & Technology Hellas
Aristides G. Eliopoulos: National and Kapodistrian University of Athens

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Balancing maintenance of self-renewal and differentiation is a key property of adult stem cells. The epigenetic mechanisms controlling this balance remain largely unknown. Herein, we report that the Polycomb Repressive Complex 2 (PRC2) is required for maintenance of the intestinal stem cell (ISC) pool in the adult female Drosophila melanogaster. We show that loss of PRC2 activity in ISCs by RNAi-mediated knockdown or genetic ablation of the enzymatic subunit Enhancer of zeste, E(z), results in loss of stemness and precocious differentiation of enteroblasts to enterocytes. Mechanistically, we have identified the microRNA miR-8 as a critical target of E(z)/PRC2-mediated tri-methylation of histone H3 at Lys27 (H3K27me3) and uncovered a dynamic relationship between E(z), miR-8 and Notch signaling in controlling stemness versus differentiation of ISCs. Collectively, these findings uncover a hitherto unrecognized epigenetic layer in the regulation of stem cell specification that safeguards intestinal homeostasis.

Date: 2024
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DOI: 10.1038/s41467-024-46119-9

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