Requirement for MLL3 in p53 regulation of hepatic expression of small heterodimer partner and bile acid homeostasis

Dae Hwan Kim, Juhee Kim, Jae W. Lee

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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, MLL3Δ/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 MLL3Δ/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.

Original languageEnglish (US)
Pages (from-to)2076-2083
Number of pages8
JournalMolecular Endocrinology
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2011

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ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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