Roles of MLL4-complex in development of hypothalamic arcuate neurons

下丘脑由多个核团组成，调节对生存和繁殖至关重要的稳态。在 特别地，下丘脑弓状核（ARC）具有控制能量平衡的各种神经元， 由于其渗透性，在感知和处理外周线索方面发挥着关键作用 和周围血流的距离尽管ARC神经元在生长和能量方面起着重要作用， 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MLL 4复合物来填补这一空白。 （MLL 4-C）及其合作伙伴TF在ARC开发中的作用。MLL 4-C作为其伴侣TF的表观遗传共激活因子 通过利用其两个组蛋白H3修饰酶亚基; H3-赖氨酸4-甲基转移酶（H3 K4 MT）MLL 4 和H3 K27-脱甲基酶（H3 K27 DM）UTX。在人类中，MLL 4或UTX的突变引起发育性 疾病歌舞伎综合征（KS）的特征是独特的面部特征，小头畸形，心脏缺陷， 智力残疾、侏儒症和肥胖症。我们的初步结果表明， ARC中MLL 4-C的缺失导致ARC神经元发育缺陷，并导致身材矮小， 在人类KS中观察到的肥胖，导致了这项提议的主要假设：通过与伴侣的相互作用， TF、MLL 4-C被募集到对ARC神经元命运决定和神经突/轴突生长至关重要的基因。 生长并使用MLL 4/UTX的染色质开放活性上调其表达。使用 综合细胞和分子、生物化学、小鼠遗传学和全基因组方法，我们将对此进行测试 三个具体目标。这项研究将揭示遗传和表观遗传的基本原理 调节程序，指导ARC神经元的发展，建立MLL 4-C是一个概念， 用于治疗KS的各种病理的治疗靶点。

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.