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动态平衡。在……里面 特别是，下丘脑弓状核(ARC)有各种控制能量平衡的神经元， 由于其渗透性，繁殖和生长在感知和处理外围线索方面发挥着关键作用 以及与周围血流的接近。尽管ARC神经元在生长和能量中扮演着至关重要的角色 动态平衡，转录因子(TF)和表观遗传调节程序，协调其 人们对发展仍然知之甚少。在这项建议中，我们希望通过研究MLL4-络合物来填补这一空白 (MLL4-C)及其在ARC开发中的合作伙伴TF。MLL4-C作为其伙伴转录因子的表观共激活因子 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(H3K4MT)MLL4 和H3K27-脱甲基酶(H3K27 DM)UTX。在人类中，MLL4或UTX的突变导致发育 歌舞伎病综合征(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。我们强有力的初步结果表明，减弱的活动 ARC中MLL4-C的缺失导致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，导致了这一提议的主要假设：通过与伴侣互动 TFS、MLL4-C被招募到决定ARC神经元命运和轴突/轴突的关键基因 并利用MLL4/UTX的染色质开放活性上调其表达。使用 细胞和分子、生化、小鼠遗传学和全基因组方法的集合，我们将测试这一点 三个具体目标的假设。这项研究将揭示遗传学和表观遗传学的基本原理 指导ARC神经元发育的调节程序，建立了MLL4-C是一种 以治疗KS的各种病理为靶点。

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.