Rapid Dynamics of Signal-Dependent Transcriptional Repression by Capicua

Optogenetic perturbations, live imaging, and time-resolved ChIP-seq assays in Drosophila embryos were used to dissect the ERK-dependent control of the HMG-box repressor Capicua (Cic), which plays critical roles in development and is deregulated in human spinocerebellar ataxia and cancers. We established that Cic target genes are activated before significant downregulation of nuclear localization of Cic and demonstrated that their activation is preceded by fast dissociation of Cic from the regulatory DNA. We discovered that both Cic-DNA binding and repression are rapidly reinstated in the absence of ERK activation, revealing that inductive signaling must be sufficiently sustained to ensure robust transcriptional response. Our work provides a quantitative framework for the mechanistic analysis of dynamics and control of transcriptional repression in development. •ERK signaling in the Drosophila embryo antagonizes repression in a two-step process•ERK activation leads to rapid loss of a transcriptional repressor from the DNA•Transcriptional repression is reestablished once signal is removed•Signal must persist for proper gene expression and pattern formation Using optogenetics, the MS2-MCP system, and ChIP-seq techniques, Keenan et al. investigate the dynamic transcriptional response of ERK signaling in the early Drosophila embryo. They show that ERK signaling relieves repression of genes on a short timescale and that repression can return when signal is removed.