Development of a Chemical Biology Toolbox to Investigate Histone Monoaminylation
开发用于研究组蛋白单胺化的化学生物学工具箱
基本信息
- 批准号:10711189
- 负责人:
- 金额:$ 38.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AdultBindingBiochemicalBiologyBrainCategoriesCell Fate ControlCellsChemicalsChromatinChromatin StructureComplexDevelopmentDopamineEnzymatic BiochemistryEnzymesEpigenetic ProcessExcisionGenesGenetic TranscriptionGlutamineHistone CodeHistonesIn VitroLabelMediatingMetabolismModificationN-terminalNeuronsNeurosciencesNeurotransmittersPeptidesPeriodicityPlayPost-Translational Protein ProcessingProteinsPsychologyReaderRegulationResearchRoleSeriesSerotoninamidationdesignepigenetic markerepigenetic regulationgut microbiomein vivomonoamineneuralnovelprogramsthioestertranscription factortransglutaminase 2
项目摘要
The dynamics of covalent post-translational modifications (PTMs) on histones are a key mechanism in epigenetic
regulation. Histone PTMs (also known as the “histone code”) are dynamically introduced and removed by “writer”
and “eraser” enzymes, while the recognition of these PTM makers by “reader” proteins controls the activation
and suppression of specific genes, motivating downstream epigenetic effects. Histone monoaminylation (i.e., H3
serotonylation and dopaminylation) is a newly identified epigenetic marker that plays an important role in
regulating neuronal transcription, both during development and in the adult brain. Transglutaminase 2 (TGM2)
has been proved to serve as the writer enzyme for this emerging histone PTM, which installs serotonin or
dopamine onto the N-terminal glutamine residue of H3 (i.e., H3Q5) through transamidation. However, the eraser
and reader for H3Q5 monoaminylation still remain elusive. In our recent study, we applied chemical biology
approaches to understand the dynamic control of histone monoaminylation and unexpectedly discovered that
the installation, removal, and replacement of this modification are all mediated by a single enzyme, TGM2. The
biochemical mechanism of this novel regulation is attributed to the formation of a reactive thioester complex
between TGM2 and H3 that can be attacked by nucleophiles (such as diverse monoamine metabolites). Based
on this unique enzymology, we identified an unreported histone monoaminylation, H3Q5 histaminylation, and
found that this new epigenetic marker promotes neural rhythmicity through epigenetic regulations. In this
research program, we will develop a series of chemical probes that can orthogonally label and enrich different
histone monoaminylations. Utilizing these probes, we will identify new types of monoaminylations (especially the
ones caused by gut microbiome-derived monoamines) both in vitro and in vivo. Thereafter, we will demonstrate
the pathophysiological roles of these epigenetic makers. We will also design and synthesize photocrosslinker-
containing monoaminylated peptides as chemical baits to covalently capture possible readers that recognize and
bind the target monoaminylations. The epigenetic functions of these identified readers will be further validated
both in vitro and in vivo. Finally, we will employ the chemical probes developed in this study to characterize the
non-histone targets (such as transcription factors) of monoaminylations and elucidate their potential roles in
epigenetics and chromatin biology. Together, these findings will expand the categories of histone code and open
a new door towards understanding the interplay between monoamine metabolism (from either host cells or gut
microbiome) and cell fate regulation.
组蛋白的共价翻译后修饰(ptm)动力学是表观遗传的一个关键机制
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Epigenetic meets metabolism: novel vulnerabilities to fight cancer.
- DOI:10.1186/s12964-023-01253-7
- 发表时间:2023-09-21
- 期刊:
- 影响因子:0
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