Combinatorial Action of Temporally Segregated Transcription Factors

Combinatorial action of transcription factors (TFs) with partially overlapping expression is a widespread strategy to generate novel gene-expression patterns and, thus, cellular diversity. Known mechanisms underlying combinatorial activity require co-expression of TFs within the same cell. Here, we describe the mechanism by which two TFs that are never co-expressed generate a new, intersectional expression pattern in C. elegans embryos: lineage-specific priming of a gene by a transiently expressed TF generates a unique intersection with a second TF acting on the same gene four cell divisions later; the second TF is expressed in multiple cells but only activates transcription in those where priming occurred. Early induction of active transcription is necessary and sufficient to establish a competent state, maintained by broadly expressed regulators in the absence of the initial trigger. We uncover additional cells diversified through this mechanism. Our findings define a mechanism for combinatorial TF activity with important implications for generation of cell-type diversity.