Collaborative repressive action of the antagonistic ETS transcription factors Pointed and Yan fine-tunes gene expression to confer robustness inDrosophila

The acquisition of cellular identity during development depends on precise spatiotemporal regulation of gene expression, with combinatorial interactions between transcription factors, accessory proteins and the basal transcription machinery together translating complex signaling inputs into appropriate gene expression outputs. The Drosophila ETS family transcription factors Yan and Pointed, whose opposing repressive and activating inputs orchestrate numerous cell fate transitions downstream of receptor tyrosine kinase signaling, provide one of the premier systems for studying this process. Current models describe the differentiative transition as a switch from Yan-mediated repression to Pointed-mediated activation of common target genes. We describe here a new layer of regulation whereby Yan and Pointed co-occupy regulatory elements to coordinately repress gene expression, with Pointed unexpectedly required for the genome-wide occupancy of both Yan and the corepressor Groucho. Using even-skipped as a test-case, synergistic genetic interactions between Pointed, Groucho, Yan and components of the RNA polymerase II pausing machinery suggest Pointed integrates multiple scales of repressive regulation to confer robustness. We speculate that this mechanism may be used broadly to fine-tune the expression of many developmentally critical genes.