The role of JADE in HBO complexes

JADE 在 HBO 综合体中的角色

• 批准号: 10400946
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400946
• 关键词: Acetylation; Acetyltransferase; Affinity; Binding; Biochemical; Biological; Biological Assay; Biological Process; Calorimetry; Cell physiology; Cellular biology; Chromatin; Complex; Crystallization; DNA; DNA Binding; Development; Disease; Epigenetic Process; Etiology; Fluorescence; Fluorescence Microscopy; Fluorescence Resonance Energy Transfer; Genes; Genetic Transcription; Hematological Disease; Hematology; Hematopoietic System; Histone Acetylation; Histone H3; Histones; Human; Impairment; In Vitro; Lead; Length; Light; 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

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 JADE是人类赖氨酸乙酰转移酶(KAT)HBO复合体的核心亚单位， 在转录和发育程序的调节中至关重要，并与 血液学异常。翡翠是HBO综合体正常运作所必需的， 然而，它在这些复合体中的作用尚不清楚。玉石包含三个相邻的锌指， 可以具有集成功能。既不是功能关系也不是结构组织 玉锌指的成分是已知的。我们最近的研究表明，锌 Jade的手指识别组蛋白尾巴和DNA，揭示了HBO和DNA之间的新联系 介导的乙酰化和染色质上的络合物组装。我们的主要假设是 翡翠锌指的染色质结合活性是连接HBO络合物所必需的 活性转录基因的启动子和复合体的KAT选择性。我们寻求 确定翡翠的分子机制、结构基础和功能意义 与染色质接触。我们将使用体外和体内互补的组合 方法，集成结构、生化、分子生物学和细胞生物学工具以获得 深入了解翡翠锌指盒在HBO复合体的生物功能中的作用。 这项研究对于理解糖尿病的表观遗传机制具有重要意义。 乙酰转移酶刺激转录激活。阐明该基因的分子基础 JADE/HBO-染色质的相互作用对于更好地了解糖尿病的病因也是必不可少的 由异常乙酰化引起的血液病，可能为 开发治疗或预防这些疾病的新疗法。