In 2003, we published a landmark paper describing purification of the first mammalian complexes containing histone H3-lysine 4-methyltransferases (H3K4MTs) (Mol Cell Biol 23:140, 2003). We have shown that these complexes contain either the H3K4MT MLL3 or its paralog MLL4/KMT2D (PNAS 103:15392, 2006). Other groups have subsequently shown that these complexes also contain the H3K27-demethylase UTX/KDM6A. We have pioneered dissecting the physiological roles of these MLL3/UTX- and MLL4/UTX-complexes ever since.

These complexes are associated with two prominent human disorders. Somatic mutations of the MLL3, MLL4, and UTX genes have been found in diverse human cancers, uncovering their tumor suppressor function. Our MLL3/4/UTX mutant mice are susceptible to developing a variety of tumors (e.g., PNAS 106:8513, 2009). Further, mutations in the MLL4 and UTX genes have been found to cause a human congenital developmental disorder, named Kabuki syndrome, that affects many parts of the body. Our MLL4/UTX mutant mice phenocopy various deficits of Kabuki patients, including congenital heart defects (Dev Cell 22:25, 2012).   

We strive to define the roles of MLL3/4 complexes in diverse metabolic processes (particularly in the newly emerging theme for interplays between diet and tumorigenesis; e.g., PNAS108:12266, 2011, Mol Endo 25:2076, 2011). We also wish to define the genome-wide regulatory network of MLL4/UTX-complex underlying various developmental deficits in Kabuki syndrome.

Welcome to Jae W. Lee’s Lab

at OHSU, Portland, Oregon

Gene Regulation in Metabolism and Kabuki Syndrome