Enhancers integrate combinatorial inputs from sequence-specific transcription factors (TFs) and their activity must be calibrated to achieve precise spatiotemporal control of transcript dosage. Here we demonstrate that the sequence-specific repressors SNAI1 and SNAI2 (i.e. SNAIL and SLUG) quantitatively tune enhancer activity. In human neural crest cells, SNAI1/2 occupy a subset of active enhancers, where their depletion increases H3K27ac, chromatin accessibility, and enhancer regulatory potential. Changes in SNAI1/2 binding motifs contribute to enhancer divergence between human and chimpanzee, suggesting an evolutionary role for the repressor-mediated tuning. Single-molecule chromatin profiling using Deaminase-Assisted Fiber-seq (DAF-seq) reveals that individual enhancers toggle between an ensemble of open and nucleosome-dense chromatin states. While transcriptional activators increase the fraction of the open states, SNAI1/2 shift the equilibrium toward nucleosome-occupied states. This impedes binding of activator TFs, without fully repressing the enhancer. We propose that SNAI1/2 function as a molecular dimmer switch, modulating nucleosome dynamics to calibrate enhancer output.
Ichino, L., Brennan, K. J., Mallory, B. J., Swigut, T., Bohaczuk, S. C., Mohammed, J., Mudeppa, D. G., Tabatabaee, S., Ni, C., Stergachis, A. B., Wysocka, J.
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