Targeting acetylated histone H4 by MLL4

项目摘要 表观遗传机制在衰老中起着关键作用，并在与年龄相关的疾病中被发现失控 疾病，包括神经退行性疾病和癌症。变化的主要指标 组蛋白H4的赖氨酸16(H4K16ac)在老化过程中发生在染色质中，a 在健康的老年大脑中重新分布和提高的修饰，但在 阿尔茨海默氏症。在分子水平上，H4K16ac参与了一系列基本的 细胞过程，包括高阶染色质解压和折叠，DNA损伤 修复和基因表达。尽管H4K16ac的重要性很高，但人们对其知之甚少 结合这个标记的蛋白质配体。我们最近的研究确定了植物的同源结构域Finger 6 组蛋白甲基转移酶MLL4(MLL4PHD6)作为H4K16ac的选择性效应器(或阅读器)。 MLL4识别H4K16ac的分子机制尚不清楚，将 在拟议的研究中予以澄清。我们假设H4K16ac的选择性靶标 通过在特定的基因组位置激活MLL4是转录激活MLL4靶基因所必需的 这种相互作用提供了MLL4之间的一种新的功能联系，MLL4甲基化赖氨酸4 组蛋白H3(H3K4)和产生H4K16ac的乙酰转移酶MOF。我们试图定义 以前未被描述的串扰的分子基础和功能意义 在重要的组蛋白标记之间。这些研究是我们理解生理学的基础 与H4K16ac的写作和阅读相关的活动，也是更好地 了解人类年龄相关疾病的病因，包括阿尔茨海默病和其他 神经退行性疾病。

Project Summary Epigenetic mechanisms play a pivotal role in aging and are found disregulated in age-related disorders, including neurodegenerative diseases and cancer. The major indicator of alterations occurred in chromatin during aging is acetylation of lysine 16 of histone H4 (H4K16ac), a modification that is redistributed and raised in the healthy aged brain but is considerably lost in Alzheimer’s disease. On the molecular level, H4K16ac is involved in a wide array of fundamental cellular processes, including higher-order chromatin decompaction and folding, DNA damage repair, and gene expression. Despite the high importance of H4K16ac, very little is known about protein ligands that bind this mark. Our recent studies identified the plant homeodomain finger 6 of the histone methyltransferase MLL4 (MLL4PHD6) as a selective effector (or reader) of H4K16ac. The molecular mechanism underlying the recognition of H4K16ac by MLL4 is unknown and will be elucidated in the proposed studies. We hypothesize that the selective targeting of H4K16ac by MLL4 at specific genomic sites is necessary for transcriptional activation of MLL4 target genes and that this interaction provides a novel functional link between MLL4 that methylates lysine 4 of histone H3 (H3K4) and the acetyltransferase MOF that produces H4K16ac. We seek to define the molecular basis and functional significance of the previously uncharacterized crosstalk between vital histone marks. These studies are fundamental to our understanding of physiological activities associated with ‘writing and reading’ H4K16ac and are also essential to better understand the etiology of human age-related illnesses, including AD and other neurodegenerative disorders.