Targeted DamID in C. elegans reveals a direct role for LIN-22 and NHR-25 in antagonizing the epidermal stem cell fate

Transcription factors are key players in gene networks controlling cell fate specification during development. In multicellular organisms, they display complex patterns of expression and binding to their targets, hence, tissue specificity is required in the characterization of transcription factor–target interactions. We introduce here targeted DamID (TaDa) as a method for tissue-specific transcription factor target identification in intact Caenorhabditis elegans animals. We use TaDa to recover targets in the epidermis for two factors, the HES1 homolog LIN-22, and the NR5A1/2 nuclear hormone receptor NHR-25. We demonstrate a direct link between LIN-22 and the Wnt signaling pathway through repression of the Frizzled receptor lin-17. We report a direct role for NHR-25 in promoting cell differentiation via repressing the expression of stem cell–promoting GATA factors. Our results expand our understanding of the epidermal gene network and highlight the potential of TaDa to dissect the architecture of tissue-specific gene regulatory networks.