Temporospatial induction of homeodomain gene cut dictates natural lineage reprogramming

• Main Authors: Ke Xu, Xiaodan Liu, Yuchun Wang, Chouin Wong, Yan Song
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2018-05-01
• Series: eLife
• Subjects: in vivo lineage reprogramming; temporospatial integration; enhancer-promoter looping; Wnt/Wingless signaling; ecdysone signaling pathway; organ-specific progenitor
• Online Access: https://elifesciences.org/articles/33934

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 Drosophila 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 cut expression in a subset of midgut progenitors and reprogram them into renal progenitors. Molecularly, ecdysone-induced temporal factor Broad physically interacts with cut enhancer-bound Wnt pathway effector TCF/β-catenin and likely bridges the distant enhancer and promoter region of cut through its self-association. Such long-range enhancer-promoter looping could subsequently trigger timely cut 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.