Efficient trans-differentiation/ de-differentiation of mature intestinal cells in adult Drosophila midgut by depleting a single transcription factor
The manipulation of cell identity by reprograming holds immense potential in regenerative medicine, but is often limited by the inefficient acquisition of fully functional cells. This problem can potentially be resolved by better understanding the reprogramming process using in vivo genetic models, which are currently scarce. Here we report that both enterocytes (ECs) and enteroendocrine cells (EEs) in adult Drosophila midgut show a surprising degree of cell plasticity. Depleting the transcription factor Tramtrack in the differentiated ECs can initiate Prospero-mediated cell transdifferentiation leading to EE-like cells. On the other hand, depletion of Prospero in the differentiated EEs leads to the loss of EE-specific transcription programs, allowing cell cycle re-entry or differentiation into ECs. We found that intestinal progenitor cells, ECs, and EEs have a similar chromatin accessibility profile, suggesting that cell plasticity is enabled by pre-existing chromatin accessibility with switchable transcription programs. In a pilot genetic screen using this system, we found that cell lineage confliction and epigenetic memory were potential barriers during the EC-to-EE transdifferentiation. The establishment of this genetically tractable in vivo model should facilitate mechanistic investigation of cell plasticity at the molecular and genetic level. Overall design: Chromatin accessibility analysis by ATAC-seq, using FACS sorted normal EC, EE, progenitor and transformed EE-like and progenitor like cells