Enhancer Tuning by Sequence-Specific Repressors
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 regulate the expression of genes by controlling the activity of transcription factors (TFs). To fine-tune their activity, enhancers require calibration, which is achieved by sequence-specific repressors. In a study focusing on human neural crest cells, researchers demonstrated that repressors SNAI1 and SNAI2 modulate enhancer activity quantitatively.
The presence of SNAI1/2 in a subset of active enhancers leads to an increase in H3K27ac, chromatin accessibility, and enhancer regulatory potential upon their depletion. The study also reveals that changes in SNAI1/2 binding motifs contribute to enhancer divergence between human and chimpanzee species, suggesting that these repressors play an evolutionary role in the tuning of enhancer activity.
Using single-molecule chromatin profiling through Deaminase-Assisted Fiber-seq (DAF-seq), the researchers observed that individual enhancers switch between open and nucleosome-dense chromatin states. While transcriptional activators favor the open chromatin states, SNAI1/2 shift the equilibrium towards nucleosome-occupied states. This mechanism impedes the binding of activator TFs without fully repressing the enhancer.
The researchers propose that SNAI1/2 function as a molecular dimmer switch, modulating nucleosome dynamics to accurately calibrate enhancer output.
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