A bHLH interaction code controls bipotential differentiation and self-renewal in the Drosophila gut

Multipotent adult stem cells balance self-renewal with differentiation into various cell types. How this balance is regulated at the transcriptional level is poorly understood. Here, we show that a network of basic helix-loop-helix (bHLH) transcription factors controls both stemness and bipotential differentiation in the Drosophila adult intestine. We find that homodimers of Daughterless (Da), a homolog of mammalian E proteins, maintain self-renewal of intestinal stem cells (ISCs), antagonizing the enteroendocrine fate promoted by heterodimers of Da and Scute (Sc; homolog of ASCL). The HLH factor Extramacrochaetae (Emc; homologous to Id proteins) promotes absorptive differentiation by titrating Da and Sc. Emc prevents the committed absorptive progenitor from dedifferentiating, underscoring the plasticity of these cells. Switching physical interaction partners in this way enables the active maintenance of stemness while priming stem cells for differentiation along two alternative fates. Such regulatory logic is likely operative in other bipotent stem cell systems.