The role of JADE in HBO complexes

JADE 在 HBO 综合体中的角色

基本信息

批准号：
10625974
负责人：
TATIANA G KUTATELADZE
金额：
$ 46.11万
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：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625974
关键词：
Acetylation Acetyltransferase Affinity Binding Biochemical Biological Biological Assay Biological Process Calorimetry Cell physiology Cellular biology Chromatin Complex DNA DNA Binding Development Disease Epigenetic Process Etiology Fluorescence Fluorescence Microscopy Fluorescence Resonance Energy Transfer Genetic Transcription Hematological Disease Hematology Hematopoietic System Histone Acetylation Histone H3 Histones Human Impairment In Vitro Length Link Lysine Measures Mediating Modeling Molecular Molecular Biology NMR Spectroscopy Nucleosome Core Particle Nucleosomes Peptides Play Post-Translational Protein Processing Regulation Role Signal Pathway Signal Transduction Structure Tail Therapeutic Titrations Transcriptional Activation Transcriptional Regulation Western Blotting X-Ray Crystallography Zinc Fingers chromatin immunoprecipitation design human disease in vivo insight leukemia loss of function mutant novel novel therapeutics prevent programs promoter screening solid state nuclear magnetic resonance tool

项目摘要

Project Summary JADE is a core subunit of the major human lysine acetyltransferase (KAT) HBO complexes, essential in the regulation of transcriptional and developmental programs and linked to haematological abnormalities. JADE is required for proper functioning of the HBO complexes, however its role in the complexes remains unclear. JADE contains three adjacent zinc fingers that may have an integrated function. Neither the functional relationship nor structural organization of components of the JADE zinc fingers are known. Our recent studies demonstrate that the zinc fingers of JADE recognize both histone tails and DNA, revealing a novel link between HBO- mediated acetylation and the complex assembly on chromatin. Our major hypothesis is that the chromatin-binding activity of the zinc fingers of JADE is necessary to bridge the HBO complexes to promoters of actively transcribed genes and for the KAT selectivity of the complex. We seek to determine the molecular mechanism, the structural basis and functional significance of the JADE engagement with chromatin. We will use a combination of complementary in vitro and in vivo approaches, integrating structural, biochemical, molecular biology, and cell biology tools to gain insight into the role of the JADE zinc finger cassette in biological functions of the HBO complexes. This study is of fundamental importance for understanding the epigenetic mechanisms of acetyltransferase-stimulated transcriptional activation. Elucidating the molecular basis of the JADE/HBO-chromatin interaction is also essential to better understand the etiology of haematological diseases caused by aberrant acetylation and may pave the way for the development of novel therapies to treat or prevent these diseases.

项目摘要玉是主要人类赖氨酸乙酰转移酶（KAT）HBO复合物的核心亚基，在调节转录和发展计划中至关重要的血液学异常。玉是HBO复合物的正确运行所必需的，但是，其在复合物中的作用尚不清楚。玉包含三个相邻的锌指可能具有集成功能。功能关系也不已知玉锌指的组件。我们最近的研究表明锌玉的手指识别组蛋白的尾巴和DNA，揭示了HBO-之间的新型联系。介导的乙酰化和染色质上的复合体组装。我们的主要假设是翡翠锌指的染色质结合活性对于桥接HBO复合物是必需的主动转录基因的启动子和复合物的Kat选择性。我们寻求确定玉器的分子机制，结构基础和功能意义与染色质互动。我们将结合体外和体内互补的组合方法，整合结构，生化，分子生物学和细胞生物学工具深入了解玉锌指盒在HBO复合物生物学功能中的作用。这项研究对于理解表观遗传机制至关重要乙酰转移酶刺激的转录激活。阐明的分子基础玉/HBO染色质相互作用对于更好地了解病因也至关重要由异常乙酰化引起的血液学疾病，可能为开发新疗法以治疗或预防这些疾病。