SEUNGHEE LEE'S LAB
Gene regulation in neural development,
embryonic stem cells, metabolism and tumoregenesis
RESEARCH INTERESTS
1. To define gene regulatory networks that govern neuronal differentiation and cell fate specification during the development of the central nervous system
Our main projects have been focused on one of the most challenging issues in neural development, which is to understand how billions of different neuronal cell types are generated from a relatively small pool of neural stem cells. To tackle this issue, we chose to work on a well-defined model system of the developing embryonic spinal cord neurons, particularly motor neurons and associated interneurons that impact all aspects of our daily life, including breathing. Specifically, we aimed to understand the molecular basis for i) how neural stem cells develop into motor neurons as opposed to other related cell fates ii) how motor neurons mature and acquire their motor neuron properties, including axonal growth and neural transmitter fate specification, and iii) how later motor neuron columnar fate specification is determined. In particular, we have been striving to address a full range of gene regulation layers, including how upstream signaling cues converge on the function of key transcription factors and their specific transcriptional coregulators, involvement of various post-translational modifications in key gene regulators, and the fundamental question of how genetic regulation controls cell fate specifications. In addressing these issues, we have been utilizing an innovative and comprehensive ensemble of cellular, biochemical, genetic, and genome-wide approaches.
2. To define the molecular mechanism of metabolic homeostasis by epigenetic gene regulation
The second long-term research goal is to define genetic and epigenetic regulatory networks underlying metabolic homeostasis. Our efforts have been centered on a transcriptional coactivator complex named MLL4-complex (herein referred to as MLL4-C), which contains the histone H3-lysine 4-methyltransferase MLL4 and H3K27-demethylase UTX that function together to form transcriptionally active open chromatin on target genes of MLL4-C. Non-alcoholic fatty liver disease (NAFLD) is tightly associated with ‘Metabolic Syndrome’, and both are rapidly becoming a pandemic. Moreover, the circadian clock programs daily rhythms, coordinating various physiological and behavioral processes. In particular, abnormal circadian rhythms are closely linked to NAFLD, diabetes, and obesity. Many studies discovered gene regulatory program directing steatosis and core clock machineries affecting both peripheral and central metabolic regulatory cues. Despite these key findings, the epigenetic mechanisms that drive steatosis and couple clock and metabolism are still ill-defined. With the mutant mouse models of Mll4, we first revealed that MLL4-C acts as major epigenetic regulator of diverse metabolic processes including circadian control of bile acid homeostasis.
3. To define the molecular basis for development and function of hypothalamic neurons that control energy balance
The hypothalamus plays critical roles in growth, homeostasis and energy metabolism, and thus defects in hypothalamic development result in serious pathological conditions, including diabetes and obesity. Although neurons in the hypothalamic arcuate nucleus (ARC) have been well studied for their physiological action to centrally regulate various homeostatic processes that are essential to survival and reproduction, the gene regulatory network that directs their development remains poorly understood. My research group embarked on new projects to address the vital issue by specifically focusing on GHRH-neurons that direct growth and AgRP-neurons that trigger feeding. In humans, inactivation mutations of MLL4 lead to Kabuki syndrome (KS). As dwarfism is one of the major features of KS, we addressed the roles of MLL4 in directing developmental programs for GHRH-neurons using mouse models and genomic analysis.
