Roles of MLL4-complex in development of hypothalamic arcuate neurons

MLL4复合物在下丘脑弓状神经元发育中的作用

• 批准号: 9900089
• 负责人: JAE W LEE
• 金额: $ 3.45万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-19 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900089
• 关键词: Acetylation; Antibodies; Attenuated; Axon; Binding; Biochemical; Blood Circulation; CREB1 gene; Cell Nucleus; Cells; Chromatin; Complex; Cues; Data Set; Defect; Dendrites; Development; Dwarfism; Energy Metabolism; Enzymes; Epigenetic Process; Face; Feeding behaviors; Gene Expression; Genes; Genetic; Goals; Growth; Heart; Heart Abnormalities; Histone H3; Histones; Homeostasis; Human; Hypothalamic structure; Intellectual functioning disability; Kabuki Make-Up Syndrome; Knock-out; Lysine; Methylation; Methyltransferase; Microcephaly; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Names; Neurites; Neurons; Obesity; Pathology; Peripheral; Permeability; Play; Reproduction; Role; Somatotropin-Releasing Hormone; Structure of nucleus infundibularis hypothalami; Syndrome; Testing; Wild Type Mouse; axon growth; developmental disease; energy balance; feeding; genome-wide; neurite growth; neurogenesis; neuron development; postnatal; programs; recruit; therapeutic target; transcription factor; transcriptome sequencing

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.

下丘脑由多个核组成，调节对生存和繁殖至关重要的体内平衡。在 特别是，下丘脑弓状核（ARC）具有控制能量平衡的各种神经元， 繁殖和生长，并由于其渗透性而在感知和处理外周信号中发挥关键作用 以及接近外周血流。尽管 ARC 神经元在生长和能量方面发挥着重要作用 体内平衡、转录因子 (TF) 和表观遗传调控程序协调其 发展仍然知之甚少。在本提案中，我们希望通过研究 MLL4 复合体来填补这一空白 (MLL4-C) 及其在 ARC 开发中的合作伙伴 TF。 MLL4-C 充当其伙伴 TF 的表观遗传共激活因子 利用其两个组蛋白 H3 修饰酶亚基； H3-赖氨酸 4-甲基转移酶 (H3K4MT) MLL4 和 H3K27 去甲基酶 (H3K27DM) UTX。在人类中，MLL4 或 UTX 的突变会导致发育障碍 歌舞伎综合症（KS），其特征是独特的面部特征、小头畸形、心脏缺陷、 智力障碍、侏儒症和肥胖症。我们强有力的初步结果表明，减弱的活性 ARC 中 MLL4-C 的缺失会导致 ARC 神经元发育缺陷，并导致身材矮小和 在人类 KS 中观察到的肥胖，导致了该提案的主要假设：通过与伴侣互动 TF、MLL4-C 被招募到对 ARC 神经元命运决定和神经突/轴突至关重要的基因 利用 MLL4/UTX 的染色质打开活性来促进生长并上调其表达。使用 细胞和分子、生化、小鼠遗传学和全基因组方法的集合，我们将测试这个 三个具体目标的假设。这项研究将揭示遗传和表观遗传的基本原理 指导 ARC 神经元发育的调控程序，建立了 MLL4-C 是一个 治疗 KS 各种病理的治疗目标。