Tissue-specific transcription factor target identification in the Caenorhabditis elegans epidermis using targeted DamID

Transcription factors are key orchestrators of development in multicellular animals and display complex patterns of expression, as well as tissue-specific binding to targets. However, our ability to map transcription factor-target interactions in specific tissues of intact animals remains limited. We introduce here targeted DamID (TaDa) as a method to identify transcription factor targets with tissue-specific resolution in C. elegans. We focus on the epidermis as a paradigm and demonstrate that TaDa circumvents problems with Dam-associated toxicity and allows reproducible identification of putative targets. Using a combination of TaDa and single-molecule FISH (smFISH), we refine the positions of LIN-22 and NHR-25 within the epidermal gene network. We reveal direct links between these two factors and the cell differentiation programme, as well as the Wnt signalling pathway. Our results illustrate how TaDa and smFISH can be used to dissect the architecture of tissue-specific gene regulatory networks.