Temporospatial induction of homeodomain gene <i>cut</i> dictates natural lineage reprogramming.

Abstract

Understanding how cellular identity naturally interconverts with high efficiency and temporospatial precision is crucial for regenerative medicine. Here, we revealed a natural midgut-to-renal lineage conversion event during <i>Drosophila</i> metamorphosis and identified the evolutionarily-conserved homeodomain protein Cut as a master switch in this process. A steep Wnt/Wingless morphogen gradient intersects with a pulse of steroid hormone ecdysone to induce <i>cut</i> expression in a subset of midgut progenitors and reprogram them into renal progenitors. Molecularly, ecdysone-induced temporal factor Broad physically interacts with <i>cut</i> enhancer-bound Wnt pathway effector TCF/β-catenin and likely bridges the distant enhancer and promoter region of <i>cut</i> through its self-association. Such long-range enhancer-promoter looping could subsequently trigger timely <i>cut</i> transcription. Our results therefore led us to propose an unexpected poising-and-bridging mechanism whereby spatial and temporal cues intersect, likely via chromatin looping, to turn on a master transcription factor and dictate efficient and precise lineage reprogramming.