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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.

项目概要 JADE 是主要人类赖氨酸乙酰转移酶 (KAT) HBO 复合物的核心亚基，在转录和发育程序的调节中至关重要，并与血液学异常。 JADE 是 HBO 综合体正常运作所必需的，然而它在复合物中的作用仍不清楚。 JADE 包含三个相邻的锌指，可能具有集成功能。无论是功能关系还是结构组织 JADE 锌指的成分是已知的。我们最近的研究表明，锌 JADE 的手指可识别组蛋白尾部和 DNA，揭示了 HBO- 介导的乙酰化和染色质上的复杂组装。我们的主要假设是 JADE 锌指的染色质结合活性对于桥接 HBO 复合物是必需的活性转录基因的启动子以及复合物的 KAT 选择性。我们力求确定JADE的分子机制、结构基础和功能意义与染色质的结合。我们将使用互补的体外和体内的组合方法，整合结构、生化、分子生物学和细胞生物学工具来获得深入了解 JADE 锌指盒在 HBO 复合物的生物学功能中的作用。这项研究对于理解表观遗传机制具有重要意义乙酰转移酶刺激的转录激活。阐明其分子基础 JADE/HBO-染色质相互作用对于更好地了解疾病的病因也至关重要由异常乙酰化引起的血液疾病，可能为开发治疗或预防这些疾病的新疗法。