ASCOM controls farnesoid X receptor transactivation through its associated histone H3 lysine 4 methyltransferase activity

Activating signal cointegrator-2 (ASC-2), a coactivator of multiple nuclear receptors and transcription factors, belongs to a steady-state complex named ASCOM (for ASC-2 complex), which contains histone H3 lysine 4 (H3K4) methyltransferase MLL3 or its paralog MLL4. ASC-2 binds to many nuclear receptors in a ligand-dependent manner through its two LxxLL motifs. Here we show that the first LxxLL motif of ASC-2 shows relatively weak but specific interaction with the nuclear receptor farnesoid X receptor (FXR) and that ASCOM plays crucial roles in FXR transactivation. Our results reveal that ASC-2, MLL3, and MLL4 are recruited to FXR target genes in a ligand-dependent manner. We further show that the recruitment of MLL3 requires ASC-2 and that FXR ligand induces not only expression of FXR-target genes but also their H3K4 trimethylation in a manner dependent on the presence of ASC-2, MLL3, and MLL4. In addition, MLL3 and MLL4 function redundantly with FXR transactivation. Correspondingly, expression of FXR target genes is partially impaired in mice expressing an enzymatically inactivated mutant form of MLL3, and these mice show disrupted bile acid homeostasis. Overall, these results suggest that ASCOM-MLL3 and ASCOM-MLL4 play redundant but essential roles in FXR transactivation via their H3K4 trimethylation activity.