Psc and Su(z)2 safeguard intestinal stem cell identity and prevent chinmo-dependent tumorigenesis

Area of Science:

• Developmental Biology
• Epigenetics
• Stem Cell Biology

Background:

• Polycomb group (PcG) genes are crucial epigenetic regulators maintaining transcriptional repression during development.
• The function of PcG genes in adult multipotent stem cell lineages, particularly in maintaining cell identity, is not well understood.

Purpose of the Study:

• To investigate the role of Polycomb Repressive Complex 1 (PRC1) components Psc and Su(z)2 in adult Drosophila intestinal stem cells (ISCs).
• To elucidate the mechanisms by which Psc and Su(z)2 regulate ISC identity and prevent tumor formation.

Main Methods:

• Genetic manipulation of Psc and Su(z)2 in Drosophila adult midgut intestinal stem cells.
• Analysis of tumor formation, cell proliferation, and signaling pathways (JAK/STAT, Ras/MAPK, Wnt, Notch).
• Transcriptomic and chromatin accessibility profiling to assess gene expression and epigenetic changes.

Main Results:

• Simultaneous loss of Psc and Su(z)2 in ISCs induced tumor formation characterized by proliferative, undifferentiated cells.
• Tumor cells exhibited suppressed canonical proliferation and differentiation pathways but showed ectopic activation of neural lineage genes, including the oncogene chinmo.
• The tumor phenotype was specific to Psc and Su(z)2 loss, independent of canonical PRC1 function, and chinmo was required for tumor overgrowth.

Conclusions:

• Psc and Su(z)2 play a noncanonical, context-specific tumor-suppressive role in adult ISCs.
• These PcG genes are essential for maintaining ISC identity and preventing lineage deviation towards neural fates.
• Disruption of Psc/Su(z)2 function leads to intestinal tumorigenesis by impairing differentiation and promoting aberrant lineage plasticity.