The hypothalamus, consisting of multiple nuclei, regulates homeostasis crucial for survival and reproduction. In particular, the hypothalamic arcuate nucleus (ARC) has various neurons that control energy balance, reproduction, and growth and play key roles in sensing and processing peripheral cues due to its permeability and proximity to the peripheral bloodstream. Despite the vital roles of ARC neurons in the growth and energy homeostasis, the transcription factors (TFs) and epigenetic regulatory programs that orchestrate their development remain poorly understood. In this proposal, we wish to fill this gap by studying MLL4-complex (MLL4-C) and its partner TFs in ARC development. MLL4-C acts as an epigenetic coactivator of its partner TFs by utilizing its two histone H3-modifying enzyme subunits; the H3-lysine 4-methyltransferase (H3K4MT) MLL4 and the H3K27-demethylase (H3K27DM) UTX. In humans, mutations in MLL4 or UTX cause a developmental disorder Kabuki syndrome (KS) characterized by a unique facial feature, microcephaly, heart defects, intellectual disability, dwarfism and obesity. Our strong preliminary results suggest that the attenuated activity of MLL4-C in the ARC results in deficits in ARC neuronal development and contributes to the short stature and obesity observed in human KS, leading to the major hypothesis of this proposal: By interacting with partner TFs, MLL4-C is recruited to the genes critical for ARC neuronal fate determination and neurite/axonal growth and upregulates their expression using the chromatin-opening activities of MLL4/UTX. Using an ensemble of cell and molecular, biochemical, mouse genetics, and genome-wide approaches, we will test this hypothesis in three specific aims. This study will reveal fundamental principles of genetic and epigenetic regulatory programs that direct ARC neuronal development, establishing the concept that MLL4-C is a therapeutic target to treat various pathologies of KS.
In this proposal, we will uncover the genetic and epigenetic mechanisms that direct the development of the hypothalamic arcuate neurons that control feeding, energy expenditure and growth. We will accomplish this goal by studying the epigenetic coactivator named MLL4 (aka KMT2D) and its partner transcription factors.