Crucial roles of mixed‐lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice

Abstract

The histone H3-lysine-4 methyltransferase mixed-lineage leukemia 3 (MLL3) and its closest homolog, MLL4 (aka KMT2D), belong to two homologous transcriptional coactivator complexes, named MLL3 and MLL4 complexes, respectively. MLL3 plays crucial roles in multiple metabolic processes. However, the physiological roles of MLL4 in metabolism and the relationship between MLL3 and MLL4 in metabolic gene regulation are unclear. To address these issues, we analyzed the phenotypes of newly generated MLL4 mutant mice, along with MLL3 mutant and MLL3;MLL4 compound mutant mice. We also performed comparative genome-wide transcriptome analyses in livers of MLL3, MLL4, and MLL3;MLL4 mutant mice. These analyses revealed that MLL3 and MLL4 complexes are key epigenetic regulators of common metabolic processes and the hepatic circadian clock. Subsequent mechanistic analyses uncovered that MLL3/4 complexes function as pivotal coactivators of the circadian transcription factors (TFs), retinoid-related orphan receptor (ROR)-α and -γ, in the hepatic circadian clock. Consistent with disturbed hepatic clock gene expression in MLL4 mutant mice, we found that rhythmic fluctuation of hepatic and serum bile acid (BA) levels over the circadian cycle is abolished in MLL4 mutant mice. Our analyses also demonstrate that MLL4 primarily impinges on hepatic BA production among several regulatory pathways to control BA homeostasis. Together, our results provide strong in vivo support for important roles of both MLL3 and MLL4 in similar metabolic pathways. Conclusion: Both MLL3 and MLL4 complexes act as major epigenetic regulators of diverse metabolic processes (including circadian control of bile acid homeostasis) and as critical transcriptional coactivators of the circadian TFs, RORs.

The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy

“…Previous studies demonstrated that the expression levels of Smad3, GATA4 and EGR1 were downregulated in the livers of MLL3-deficient mice, which was detected by RNA-seq and microarray (14,25). Furthermore, we found that H3K4me1 and H3K4me3 had multiple binding sites at the genomes of these three genes via analysis of the ChIPsequence data released in the ENCODE database.…”

“…Several studies have demonstrated that some HMTs are profoundly involved in the development of heart and cardiac remodeling (2,3,15 (14,25). As we have verified that MLL3 expression level was upregulated in the DCM hearts compared with donor hearts, we hypothesized that the expression levels of Smad3, GATA4 and EGR1 would increase in the hearts of DCM melanoma and pancreatic cancer (37)(38)(39)(40).…”

The cancer COMPASS: navigating the functions of MLL complexes in cancer

“…Conditional knockouts of Mll2/Kmt2D with or without simultaneous knock-out of Mll3/Kmt2C revealed that Mll3/Kmt2C could partially compensate for loss of Mll2/Kmt2D in adipogenesis. A partial genetic redundancy between Mll3/Kmt2C and Mll2/Kmt2D was confirmed in a recent study comparing both single and compound Mll3/Kmt2C þ/-and Mll2/Kmt2D þ/-heterozygous deletion mice (123). Gene expression profiling in these mice revealed that both Mll3/Kmt2C and Mll2/Kmt2D were important for circadian-clock control and similar metabolic pathways in hepatic cells, including bile acid and lipid synthesis.…”

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

“…This increased NADH/NAD + ratio may relate to a previously described propensity of Kmt2d +/βGeo mice toward biochemical processes predicted to produce NADH, including beta-oxidation, and a resistance to high-fat-diet-induced obesity (27). If this exaggerated BHB elevation holds true in patients with KS, the KD may be a particularly effective treatment strategy for this patient population; however, this remains to be demonstrated.…”