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<p>Intestinal stem cells (ISCs) continuously renew the gut epithelium by producing specialised cell types, yet the mechanisms that couple ISC renewal with lineage commitment remain poorly characterised. Here, we identify a self-limiting transcriptional program, mediated by the zinc-finger transcription factor <i>Chronophage</i> (<i>Cph</i>), that promotes both ISC maintenance and differentiation into enteroendocrine (EE) cells in the <i>Drosophila</i> midgut. <i>Cph</i> expression is transiently induced by the proneural factor <i>scute</i> at the onset of ISC-to-EE specification. Genetic and single-cell transcriptomic approaches revealed that <i>Cph</i> is required to reprogramme ISCs and sustain normal lifespan. Cph binds to genes involved in proliferation and differentiation, and directly represses its own expression. This autoinhibitory feedback safeguards ISCs from accumulating autophagosomes and undergoing cell death, thus preserving ISC function. Our findings uncover a key regulatory mechanism that balances stem cell maintenance and differentiation, highlighting principles relevant to regenerating tissues.</p>

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Autoinhibitory feedback preserves intestinal stem cell maintenance and fate commitment

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月20日

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  • Siamak Redhai,
  • Nick Hirschmüller,
  • Tianyu Wang,
  • Tyler Jackson,
  • Stefan Peidli,
  • Erica Valentini,
  • Shivohum Bahuguna,
  • Svenja Leible,
  • Sarina Möller,
  • Christina Ko,
  • Michaela Holzem,
  • Sviatoslav Kharuk,
  • Lea Bräckow,
  • Fillip Port,
  • David Ibberson,
  • Hongjie Le,
  • Wolfgang Huber,
  • Michael Boutros

摘要

Intestinal stem cells (ISCs) continuously renew the gut epithelium by producing specialised cell types, yet the mechanisms that couple ISC renewal with lineage commitment remain poorly characterised. Here, we identify a self-limiting transcriptional program, mediated by the zinc-finger transcription factor Chronophage (Cph), that promotes both ISC maintenance and differentiation into enteroendocrine (EE) cells in the Drosophila midgut. Cph expression is transiently induced by the proneural factor scute at the onset of ISC-to-EE specification. Genetic and single-cell transcriptomic approaches revealed that Cph is required to reprogramme ISCs and sustain normal lifespan. Cph binds to genes involved in proliferation and differentiation, and directly represses its own expression. This autoinhibitory feedback safeguards ISCs from accumulating autophagosomes and undergoing cell death, thus preserving ISC function. Our findings uncover a key regulatory mechanism that balances stem cell maintenance and differentiation, highlighting principles relevant to regenerating tissues.