Requirement for MLL3 in p53 Regulation of Hepatic Expression of Small Heterodimer Partner and Bile Acid Homeostasis

The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) belongs to a large complex that functions as a coactivator of multiple transcription factors, including the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR), a critical player in BA homeostasis. BA-activated FXR induces hepatic expression of small heterodimer partner (SHP), which in turn suppresses expression of BA synthesis genes, Cyp7a1 and Cyp8b1. Thus, MLL3(Δ/Δ) mice that express a catalytically inactive mutant form of MLL3 display increased BA levels. Recently, we have discovered a distinct regulatory pathway for BA homeostasis, in which p53 independently up-regulates SHP expression in the liver. Here, we show that the MLL3 complex is also essential for p53 transactivation of SHP. Although activated p53 signaling in MLL3(+/+) mice results in decreased BA levels through hepatic up-regulation of SHP, these changes are abolished in MLL3(Δ/Δ) mice. For both HepG2 cells and mouse liver, we also demonstrate that p53 directs the recruitment of different components of the MLL3 complex to the p53-response elements of SHP and that p53-dependent H3-lysine-4-trimethylation of SHP requires MLL3. From these results, we conclude that both FXR- and p53-dependent regulatory pathways for SHP expression in BA homeostasis require the MLL3 complex; thus, the MLL3 complex is likely a master regulator of BA homeostasis. Using a common coregulator complex for multiple transcription factors, which independently control expression of the same gene, might be a prevalent theme in gene regulation and may also play critical roles in assigning a specific biological function to a coregulator complex.