Targeting acetylated histone H4 by MLL4

MLL4 靶向乙酰化组蛋白 H4

基本信息

批准号：
10228868
负责人：
TATIANA G KUTATELADZE
金额：
$ 51.19万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228868
关键词：
Acetylation Acetyltransferase Affinity Aging Alzheimer&apos s Disease Binding Binding Proteins Biological Biological Assay Calorimetry Cell physiology Chromatin Complex Crystallization DNA Repair Disease Epigenetic Process Etiology Fingers Fluorescence Gene Expression Genetic Transcription Genomics Histone Acetylation Histone H3 Histone H4 Histones Human In Vitro Length Light Link Lysine Malignant Neoplasms Measures Mediating Methyltransferase Modeling Modification Molecular Mutagenesis Neurodegenerative Disorders PHD Finger Pathogenicity Peptides Physiological Plants Play Post-Translational Protein Processing Protein Acetylation Reader Reading Role Signal Transduction Site Specificity Structure Tail Therapeutic Titrations Transcriptional Activation Western Blotting Writing age related aging brain chromatin immunoprecipitation design gene interaction histone methyltransferase histone modification homeodomain human disease in vivo insight loss of function mutant novel prevent screening

项目摘要

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.

项目概要表观遗传机制在衰老过程中发挥着关键作用，并且在与年龄相关的疾病中不受调节疾病，包括神经退行性疾病和癌症。衰老过程中染色质中发生的现象是组蛋白 H4 (H4K16ac) 的赖氨酸 16 的乙酰化，在健康的老年大脑中重新分配和产生的修改，但在在分子水平上，H4K16ac 涉及多种基础疾病。细胞过程，包括高阶染色质解压缩和折叠、DNA 损伤尽管 H4K16ac 非常重要，但人们对它知之甚少。我们最近的研究鉴定了植物同源结构域手指 6。组蛋白甲基转移酶 MLL4 (MLL4PHD6) 作为 H4K16ac 的选择性效应子（或读取器）。 MLL4 识别 H4K16ac 的分子机制尚不清楚，有待进一步研究。我们在拟议的研究中阐明了 H4K16ac 的选择性靶向。 MLL4 在特定基因组位点的作用对于 MLL4 靶基因的转录激活是必需的并且这种相互作用在 MLL4 之间提供了一种新的功能联系，可将赖氨酸 4 甲基化我们试图定义组蛋白 H3 (H3K4) 和产生 H4K16ac 的乙酰转移酶 MOF。先前未表征的串扰的分子基础和功能意义这些研究对于我们理解生理学至关重要。与“写作和阅读”H4K16ac 相关的活动对于更好地了解人类年龄相关疾病的病因学，包括 AD 和其他疾病神经退行性疾病。