Widespread regulatory specificities between transcriptional co-repressors and enhancers in Drosophila

Gene expression is controlled by the precise activation and repression of transcription. Repression is mediated by specialized transcription factors (TFs) that recruit co-repressors (CoRs) to silence transcription, even in the presence of activating cues. However, whether CoRs can dominantly silence all enhancers or display distinct specificities is unclear. In this work, we report that most enhancers in Drosophila can be repressed by only a subset of CoRs, and enhancers classified by CoR sensitivity show distinct chromatin features, function, TF motifs, and binding. Distinct TF motifs render enhancers more resistant or sensitive to specific CoRs, as we demonstrate by motif mutagenesis and addition. These CoR-enhancer compatibilities constitute an additional layer of regulatory specificity that allows differential regulation at close genomic distances and is indicative of distinct mechanisms of transcriptional repression.

Automated summary

This study finds that in Drosophila, most enhancers are repressed by only a subset of co-repressors (CoRs), and enhancers classified by CoR sensitivity show distinct chromatin features, function, TF motifs, and binding. Different TF motifs render enhancers more resistant or sensitive to specific CoRs, resulting in the additional layer of regulatory specificity for differential regulation at close genomic distances and indicative of distinct mechanisms of transcriptional repression.