Molecular analysis of ASH1L

ASH1L 的分子分析

• 批准号: 10640283
• 负责人: TATIANA G KUTATELADZE
• 金额: $ 37.25万
• 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: 2020-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640283
• 关键词: Acute Lymphocytic Leukemia; Acute leukemia; Affinity; Binding; Biochemical; Biological; Biological Assay; Bromodomain; Calorimetry; Cell physiology; Chromatin; Complex; Data; Development; Developmental Gene; EMSA; Epigenetic Process; Fluorescence Resonance Energy Transfer; Fluorescence Spectroscopy; Gene Family; Genes; Genetic Transcription; Hematopoietic; Hematopoietic stem cells; Histone H3; Histones; Homeobox Genes; Human; Impairment; In Vitro; Knowledge; Length; Ligands; Link; Malignant Neoplasms; Measures; Mediating; Methylation; Methyltransferase; Mixed-Lineage Leukemia; Modeling; Molecular; Molecular Analysis; Mutagenesis; Mutate; NMR Spectroscopy; Nucleosomes; PHD Finger; Pathogenicity; Peptides; Physiological; Post-Translational Protein Processing; Prognosis; Proliferating; Reader; Regulation; Research; Resolution; Role; SET Domain; Signal Pathway; Signal Transduction; Structure; Therapeutic; Therapeutic Intervention; Titrations; Transcription Elongation; Transcriptional Activation; Transcriptional Regulation; Western Blotting; X-Ray Crystallography; chromatin immunoprecipitation; design; histone methylation; in vivo; insight; leukemia; loss of function; mutant; new therapeutic target; novel; prevent; promoter; recruit; screening

Project Summary Human ASH1L (absent, small, or homeotic discs like 1) mediates proliferation and survival of hematopoietic stem cells and is often upregulated in leukemias. It is required for hematopoietic development and expression of developmental genes, including the HOX gene family. Upregulated activity of ASH1L, found in mixed lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL), is generally associated with a poor prognosis. ASH1L is a major methyltransferase that methylates histone H3, generating the epigenetic mark H3K36me2 associated with transcriptional activation and elongation. ASH1L contains a unique combination of the catalytic methyltransferase SET domain and adjacent bromodomain (BD), a PHD finger, and a BAH domain with unclear biological roles. Our recent studies reveal that the BD, PHD and BAH domains of ASH1L are epigenetic readers capable of recognizing distinctive states of histone H3. The molecular mechanisms underlying these novel functions of ASH1L are unknown and will be elucidated in the proposed studies. We hypothesize that the concomitant recognition of distinct histone states by the PHD, BD and BAH domains recruits or stabilizes ASH1L at promoters of ASH1L target genes and is necessary for the catalytic activity of ASH1L and methylation of H3K36 at these genes. We seek to understand a crosstalk between the BD, PHD and BAH domains of ASH1L and determine the molecular mechanism and functional significance of the multivalent engagement of ASH1L with chromatin. We will employ complementary in vitro and in vivo approaches to establish the molecular and structural basis and define the biological importance of histone binding by ASH1L readers. This research will provide atomic-resolution insights into ASH1L signaling pathways that may constitute new targets for therapeutic interventions and enhance our knowledge of fundamental principles underlying the epigenetic-driven gene transcription. It will also lead to a better understanding of human cancers associated with aberrant activity of ASH1L, including acute leukemias.

项目总结

项目成果

Enzymatic Reactions inside Biological Condensates.

• DOI: 10.1016/j.jmb.2020.08.009
• 发表时间: 2021-06-11
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Zhang, Yi;Narlikar, Geeta J.;Kutateladze, Tatiana G.
• 通讯作者: Kutateladze, Tatiana G.

Atypical histone targets of PHD fingers.

• DOI: 10.1016/j.jbc.2023.104601
• 发表时间: 2023-04
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Black, Joshua C.;Kutateladze, Tatiana G.
• 通讯作者: Kutateladze, Tatiana G.

Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1).

• DOI: 10.1021/acs.jmedchem.1c00430
• 发表时间: 2021-06-24
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Engelberg IA;Liu J;Norris-Drouin JL;Cholensky SH;Ottavi SA;Frye SV;Kutateladze TG;James LI
• 通讯作者: James LI

Structural basis for binding diversity of acetyltransferase p300 to the nucleosome.

• DOI: 10.1016/j.isci.2022.104563
• 发表时间: 2022-07-15
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Hatazawa, Suguru;Liu, Jiuyang;Takizawa, Yoshimasa;Zandian, Mohamad;Negishi, Lumi;Kutateladze, Tatiana G.;Kurumizaka, Hitoshi
• 通讯作者: Kurumizaka, Hitoshi

Characterization of multiple interactions between the envelope E protein of SARS-CoV-2 and human BRD4.

• DOI: 10.1016/j.xpro.2022.101853
• 发表时间: 2022-12-16
• 期刊: STAR PROTOCOLS
• 作者: Zandian, Mohamad;Jang, Suk Min;Lachance, Catherine;Acharya, Arpan;Byrareddy, Siddappa N.;Cote, Jacques;Kutateladze, Tatiana G.
• 通讯作者: Kutateladze, Tatiana G.