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.