Chromatin occupancy patterns of the ETS repressor Yan: A mechanism for buffering gene expression against noise?

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Developmental programs are driven by transcription factors that coordinate precise patterns of gene expression. While recent publications have described the importance of coordinated action of transcriptional activators at multiple cis-regulatory modules or enhancers, the contribution of sequence-specific repressors to overall regulation and robustness of gene expression has been difficult to ascertain. The Ets transcriptional repressor Yan functions as part of a conserved network downstream of receptor tyrosine kinase (RTK) signaling in Drosophila. This network displays switch-like responsiveness to RTK signaling, with the transition from a high-Yan to a low-Yan state induced by mitogen-activated protein kinase (MAPK)-mediated phosphorylation and inactivation of Yan. The ability of Yan to self-associate through a conserved sterile α motif (SAM) is essential for Yan's repressive ability, and has been suggested to allow spreading of Yan repressive complexes along chromatin. Such a mechanism has the potential to confer both signal responsiveness and robustness to the Yan network. To explore this spreading model, we compared the genome-wide chromatin binding profiles of wild-type vs. monomeric Yan. Consistent with the starting prediction, we found that wild type chromatin occupancy at genes encoding crucial developmental regulators and core signaling pathway components occurs as clusters of peaks that “spread” over multiple kilobases. However monomeric Yan, which fails to rescue a yan null mutation and displays significantly impaired repressive ability, exhibits a broadly similar occupancy profile to that of wild-type Yan, with multi-kilobase binding at developmentally important genes. This unexpected result suggests that SAM-mediated self-association does not mediate Yan recruitment to DNA or chromatin spreading, and raises the questions of why developmentally important genes require extensive Yan chromatin occupancy and how SAM-mediated polymerization might contribute to active repressive mechanisms in this context. In this Extra View article we discuss potential mechanisms by which Yan self-association and extended chromatin occupancy may contribute to robust regulation of gene expression.

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