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.

项目摘要表观遗传机制在衰老中起关键作用，发现与年龄有关疾病，包括神经退行性疾病和癌症。更改的主要指标发生在老化期间的染色质中是组蛋白H4（H4K16AC）的赖氨酸16的乙酰化，A 在健康老化的大脑中被重新分布和提出的修改，但遗忘了阿尔茨海默氏病。在分子水平上，H4K16AC参与了广泛的基本细胞过程，包括高阶染色质分解和折叠，DNA损伤修复和基因表达。尽管H4K16AC的重要性很高，但对结合此标记的蛋白质配体。我们最近的研究确定了植物同源域手指6 H4K16AC的选择性效应子（或读取器）的组蛋白甲基转移酶MLL4（MLL4PHD6） MLL4对H4K16AC识别的基础机制是未知的，将会在拟议的研究中阐明。我们假设H4K16AC的选择性靶向在特定基因组位点通过MLL4对于MLL4靶基因的转录激活是必需的并且这种相互作用提供了甲基化赖氨酸4的MLL4之间的新功能联系 Hisstone H3（H3K4）和产生H4K16AC的乙酰转移酶MOF。我们试图定义先前未表征的串扰的分子基础和功能意义在重要的Hisstone标记之间。这些研究对于我们对生理学的理解至关重要与“写作和阅读” H4K16AC相关的活动，对于更好的活动也是必不可少的了解与人类年龄有关的疾病的病因，包括AD和其他神经退行性疾病。