The role of JADE in HBO complexes

JADE 在 HBO 综合体中的角色

• 批准号: 10162659
• 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/10162659
• 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; organizational structure; 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.

项目总结