Homo- and heterodimerization of bHLH transcription factors balance stemness with bipotential differentiation in the Drosophila gut

ABSTRACT

Multipotent adult stem cells must balance self-renewal with differentiation into various mature 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 bi-potential differentiation in the Drosophila adult intestine. We find that homodimers of Daughterless (Da), homolog of mammalian E proteins, maintain the self-renewal of intestinal stem cells (ISCs), and antagonise the activity of heterodimers of Da and Scute (Sc), homolog of ASCL and a known regulator of intestinal secretory differentiation. The HLH factor Extramacrochaetae (Emc), homologous to Id proteins, promotes absorptive differentiation by titrating Da and Sc to. We further show that Emc prevents the committed absorptive progenitor (the enteroblast, EB) from de-differentiating, 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 could be recapitulated in other bipotent stem cell systems.