A UTX-MLL4-p300 Transcriptional Regulatory Network Coordinately Shapes Active Enhancer Landscapes for Eliciting Transcription

Summary Enhanceractivation is a critical step for gene activation. Here we report an epigenetic crosstalk at enhancersbetween the UTX (H3K27 demethylase)-MLL4 (H3K4 methyltransferase) complex and the histone acetyltransferasep300. We demonstrate that UTX, in a demethylaseactivity-independent manner, facilitates conversion of inactive enhancersin embryonic stem cells to an active (H3K4me1 + /H3K27ac + ) state by recruiting and coupling the enzymatic functions of MLL4 and p300. Loss of UTX leads to attenuated enhanceractivity, characterized by reduced levels of H3K4me1 and H3K27ac as well as impaired transcription. The UTX-MLL4 complex enhancesp300-dependent H3K27 acetylation through UTX-dependent stimulation of p300 recruitment, while MLL4-mediated H3K4 monomethylation, reciprocally, requires p300 function. Importantly, MLL4-generated H3K4me1 further enhancesp300-dependent transcription. This work reveals a previously unrecognized cooperativity among enhancer-associated chromatin modulators, including a unique function for UTX, in establishing an "active enhancerlandscape" and defines a detailed mechanism for the joint deposition of H3K4me1 and H3K27ac.