Summary 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.

Summary: Achieving controlled reprogramming of differentiated cells into a desired cell type would open new opportunities in stem-cell biology and regenerative medicine. Experimentation on cell reprogramming requires a model in which cell conversion can be induced and tracked individually. The tiny nematode, Caenorhabditis elegans, owing to its known cellular lineage, allows the study of direct cell type conversion with a single-cell resolution. Indeed, recent advances have shown that despite its invariant cell lineage, cellular identities can be reprogrammed, leading to cell conversion in vivo. In addition, natural transdifferentiation events occur in the worm, providing a powerful model for the study of cellular plasticity in a physiological cellular microenvironment. Here, we review pioneer studies on induced and naturally occurring reprogramming events in C. elegans and the new notions that have emerged. genesis 50:1-17, 2012. V V C 2011 Wiley Periodicals, Inc.

In vitro systems of cellular reprogramming [induced pluripotent stem (iPS) cells and direct reprogramming or transdifferentiation] are rapidly improving our repertoire of molecular techniques that can force cells in culture to change into a desired identity. However, the new frontier for regenerative medicine is in vivo cellular reprogramming, which in light of concerns about the safety of in vitro cell manipulations, is an increasingly attractive approach for regenerative medicine. Powerful in vivo approaches are currently being undertaken in the genetic model Caenorhabditis elegans. Several very distinct cell types have been induced to change or have been discovered to transform naturally, into altogether different cell types. These examples have improved our understanding of the fundamental molecular and cellular mechanisms that permit cell identity changes in live animals. In addition, the combination of a stereotyped lineage with single cell analyses allows dissection of the early and intermediate mechanisms of reprogramming, as well as their kinetics. As a result, several important concepts on in vivo cellular reprogramming have been recently developed.

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