Systemic degradation of repressive transcription factors gates gene expression and cell fate specification [CUT&RUN]

Critical among these, proteasomes allow cells to initiate gene expression, but underlying targets and regulatory mechanisms remain poorly under-stood. Here, we report that proteasomes drive systemic degradation of repressive transcription factors to constantly eject co-repressors of the TLE family from chromatin and thus broadly free transcription start sites for activator binding.

Systemic transcription factor degradation depends on the E3 ligase SCFFBXL14, which gains substrate access through constitutive complex formation with TLE co-repressors. While energetically costly, cycling co-repressors on and off chromatin is essential for stem cells to translate developmental cues into lineage-specific gene expression, a regulation that is disrupted by cancer mutations in TLE1 that impair SCFFBXL14 recognition.