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. [Display omitted] •Lineage-specific priming enables asymmetric gene expression in L/R neuron pairs•Transient, lineage-specific TFs prime a locus for later activation by a bilateral TF•An early active transcriptional state is necessary and sufficient for priming•Maintenance of asymmetric primed state occurs in a symmetric regulatory environment Studying neuronal specification in C. elegans, Charest et al. reveal that lineage-specific priming by a transiently expressed transcription factor allows activation of the primed gene by another transcription factor acting four cell divisions later. The findings suggest that the intersection of temporally segregated transcription factors contributes to cell-specific gene expression and cell diversification.