Graduate Studies Faculty
Jae W. Lee, Ph.D.
Programs:Neuroscience Graduate Program
Research Interests:» Click here for more about Dr. Lee's research
Preceptor RotationsDr. Lee has not indicated availability for preceptor rotations at this time.
Faculty MentorshipDr. Lee has not indicated availability as a mentor at this time.
Our long-term goal is to understand the transcriptional regulatory network in metabolism. We are currently pursuing two major projects.
1. MLL3/4 complexes in transcription, metabolism and cancer
Our lab purified the first mammalian transcriptional coactivator complex that methylates histone H3-lysine 4 (H3K4). This complex contains either MLL3, a H3K4-methyltransferase, or its paralogue MLL4. In contrast to lower eukaryotes which contain a single such enzyme complex, mammals have at least six similar complexes, suggesting divided labor in target genes. Indeed we showed that MLL3/4 complexes selectively target genes involved in diverse metabolic processes, such as adipogenesis and glucose/lipid homeostasis. Our recent effort has been directed at characterizing roles of MLL3/4 complexes in bile acid homeostasis.
Interestingly, MLL3/4 complexes, as opposed to other mammal complexes, also contain UTX, an enzyme that removes H3K27-methyl marks, which are linked to transcriptional activation. Thus, MLL3/4 complexes have two distinct enzymes linked to transcriptional activation, offering a unique opportunity to study the interplay between H3K4- and H3K27-methylations. Using retinoic acid receptor target genes as model systems, we are analyzing how MLL3/4 complex coordinate these two different types of methylations for transcriptional activation.
MLL3/4 complexes also function as coactivators of the tumor suppressor p53, and correspondingly different subunits of MLL3/4 complexes have been shown to be mutated in human cancers. Our MLL3 mutant mice have also been shown to develop kidney tumors. More interestingly, we have recently found that p53 directly regulates bile acid homeostasis, uncovering a critical interface between tumor suppressors and metabolic homeostasis, and that MLL3/4 complexes play important roles in this unexpected interplay. We wish to expand to explore roles of MLL3/4 complexes in cancer development and how regulation of H3K4/H3K27-methylations is integrated to the interface of tumor suppression and metabolism.
2. Central roles of glucocorticoid in metabolism
Metabolic syndrome or syndrome X is a serious health threat in modern society, which led to the recent burst of metabolic studies. However, most of the progresses in metabolic studies is centered on peripheral tissues and organs such as fat tissue, muscle and the liver, while similar efforts to understand how the central nervous system (CNS) processes peripheral metabolic cues have been limited. Using glucocorticoid, an important peripheral orexigenic cue, as a model system, we wish to tackle this important issue. From this new project, we have been gathering quite a few interesting new findings, including our discovery of the major orexigenic neuropeptide AgRP as a direct target of glucocorticoid in the hypothalamus. Our current efforts include genome-wide ChIP-seq and RNA-seq to identify direct metabolic target genes of glucocorticoid in the hypothalamus. This study, coupled with our proteomics approach to identify glucocorticoid effector molecules, should greatly advance our understand of the central metabolic function of glucocortiocid in energy balance.
1. S.Lee, D.Lee, Y.Dou, J.Lee, B.Lee, E.Kwak, Y.Kong, S.K.Lee, R.G..Roeder, and J.W.Lee. A coactivator as a target gene specificity determinant for histone H3-lysine 4 methyltransferases. Proc. Natl. Acad. Sci. USA 103: 15392-7, 2006
2. S.Lee, J.Lee, S.K.Lee, and J.W.Lee. Activating signal cointegrator-2 is an essential adaptor to recruit histone H3 lysine 4 methyltransferases MLL3 and MLL4 to the liver X receptors.Mol. Endocrinol. 22: 1312-9, 2008
3. J.Lee, P.K.Saha, Q.H.Yang, S.Lee, J.Y.Park, Y.Suh, S.K.Lee, L.Chan, R.G.Roeder, and J.W.Lee. Targeted inactivation of MLL3 histone H3-lysine-4 methyltransferase activityin the mouse reveals vital roles for MLL3 in adipogenesis. Proc. Natl. Acad. Sci. USA 105:19229-19234, 2008
5. J.Lee, D.H.Kim, S.Lee, Q.H.Yang, D.K.Lee, S.K.Lee, R.G.Roeder, and J.W.Lee. A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4. Proc. Natl. Acad. Sci. USA 106: 8513-8, 2009
6. S.Lee, D.H.Kim, Y.H.Goo, Y.C.Lee, S.K.Lee, and J.W.Lee. Crucial roles for interactions between MLL3/4 and INI1 in nuclear receptor transactivation. Mol. Endocrinol. 23: 610-9, 2009
7. D.H.Kim, J.Lee, B.Lee, and J.W.Lee. ASCOM controls farnesoid X receptor transactivation through its associated histone H3 lysine 4 methyltransferase activity. Mol. Endocrinol. 23: 1556-62, 2009
8. S.Lee, R.G.Roeder, and J.W.Lee. Roles of ASCOM-MLL3 and ASCOM-MLL4, histone H3-lysine 4 methyltransferase complexes, in nuclear receptor mediated gene transcription. Prog. Nucleic Acid Res. Mol. Biol. 2009 (invited book chapter)