Acetylation-independent mechanism for binding of ENL to intrinsically disordered regions in TAF2/6 and SNF5

Eleven-nineteen-leukemia (ENL) is a well-established epigenetic regulator essential for transcription in development and implicated in cancer. Here, we report the molecular mechanisms and functional consequences of the ENL association with components of transcriptional and chromatin remodeling complexes, TAF2, TAF6, and SNF5, and describe ENL intramolecular contacts and autoregulation. We show that the extra-terminal domain of ENL binds in an acetylation-independent manner to the hydrophobic motifs identified in intrinsically disordered regions of TAF2, TAF6, and SNF5. Genomic analysis reveals genome-wide co-occupancy of ENL and TAF2 or SNF5 on active promoters, and proteomic and transcriptomic analyses demonstrate increased tumor-associated correlations of ENL with TAF2, TAF6, and SNF5 and their coordinated co-expression patterns in several types of cancer. Our findings shed light on the mechanistic details by which ENL associates with chromatin cofactors and is autoregulated, paving the way for the development of novel ENL targeted antitumor interventions.