Molecular analysis of ASH1L
ASH1L 的分子分析
基本信息
- 批准号:10640283
- 负责人:
- 金额:$ 37.25万
- 依托单位:
- 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:2020-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAcute leukemiaAffinityBindingBiochemicalBiologicalBiological AssayBromodomainCalorimetryCell physiologyChromatinComplexDataDevelopmentDevelopmental GeneEMSAEpigenetic ProcessFluorescence Resonance Energy TransferFluorescence SpectroscopyGene FamilyGenesGenetic TranscriptionHematopoieticHematopoietic stem cellsHistone H3HistonesHomeobox GenesHumanImpairmentIn VitroKnowledgeLengthLigandsLinkMalignant NeoplasmsMeasuresMediatingMethylationMethyltransferaseMixed-Lineage LeukemiaModelingMolecularMolecular AnalysisMutagenesisMutateNMR SpectroscopyNucleosomesPHD FingerPathogenicityPeptidesPhysiologicalPost-Translational Protein ProcessingPrognosisProliferatingReaderRegulationResearchResolutionRoleSET DomainSignal PathwaySignal TransductionStructureTherapeuticTherapeutic InterventionTitrationsTranscription ElongationTranscriptional ActivationTranscriptional RegulationWestern BlottingX-Ray Crystallographychromatin immunoprecipitationdesignhistone methylationin vivoinsightleukemialoss of functionmutantnew therapeutic targetnovelpreventpromoterrecruitscreening
项目摘要
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
期刊论文数量(23)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enzymatic Reactions inside Biological Condensates.
- DOI:10.1016/j.jmb.2020.08.009
- 发表时间:2021-06-11
- 期刊:
- 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:
- 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:
- 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:
- 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:
- 影响因子:0
- 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.
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TATIANA G KUTATELADZE其他文献
TATIANA G KUTATELADZE的其他文献
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{{ truncateString('TATIANA G KUTATELADZE', 18)}}的其他基金
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