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.
Neuroscience Section, Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
Dae-Hwan
DH
Kim
Juhee
J
Kim
Jae W
JW
Lee
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin; D015870:Gene Expression; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; C452979:KMT2C protein, human; D018160:Receptors, Cytoplasmic and Nuclear; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C099713:nuclear receptor subfamily 0, group B, member 2; D004317:Doxorubicin; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; D013253:Steroid 12-alpha-Hydroxylase