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: 10168151
• 负责人: JAE W LEE
• 金额: $ 8.1万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10168151
• 关键词: Roles; MLL4; complex; development; hypothalamic; Roles; MLL4; complex; development; hypothalamic

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，调节稳态对于生存和繁殖至关重要。在 特别是，下丘脑弧形核（弧）具有控制能量平衡的各种神经元， 繁殖，增长并在感应和处理外围线索中起关键作用，因为其渗透性 和靠近周围血液。尽管弧神经元在生长和能量中起着至关重要的作用 稳态，转录因子（TFS）和表观遗传调节计划，使他们 发展仍然很少理解。在此提案中，我们希望通过研究MLL4复合物来填补这一空白 （MLL4-C）及其合作伙伴TFS在ARC开发方面。 MLL4-C充当其伴侣TFS的表观遗传共激活因子 通过利用其两个组蛋白H3修改酶亚基； H3-赖氨酸4-甲基转移酶（H3K4MT）MLL4 和H3K27-二甲基酶（H3K27DM）UTX。在人类中，MLL4或UTX中的突变引起发育 疾病的Kabuki综合征（KS），其特征是独特的面部特征，小头畸形，心脏缺陷， 智力残疾，矮人和肥胖。我们强烈的初步结果表明减毒活性 ARC中MLL4-C的MLL4-C会导致弧神经元发育缺陷，并有助于矮的身材和 在人类KS中观察到的肥胖，导致该提议的主要假设：通过与伴侣互动 TFS，MLL4-C被募集到弧神经元命运和神经元/轴突关键的基因 使用MLL4/UTX的染色质开放活性来生长并上调它们的表达。使用一个 细胞和分子，生化，小鼠遗传学和全基因组方法的合奏，我们将测试 三个特定目标的假设。这项研究将揭示遗传和表观遗传学的基本原理 指导神经元发展的监管程序，确定了MLL4-C是一个概念 治疗KS各种病理的治疗靶标。