Nutrient Regulation of Cell Physiology by O-GlcNAcylation
O-GlcNAc 酰化对细胞生理学的营养调节
基本信息
- 批准号:10668984
- 负责人:
- 金额:$ 28.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-10 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAgingAlzheimer&aposs DiseaseBindingBinding ProteinsBiological ProcessC-terminalCRISPR/Cas technologyCell NucleusCell membraneCell physiologyCellsCellular StressChemicalsChromatinChronic DiseaseCodeComplexCytoplasmCytoplasmic ProteinCytosineDNADNA Polymerase IIDarknessDevelopmentDiabetes MellitusDiseaseEatingEnzymesEtiologyGene ExpressionGenesGeneticGenetic TranscriptionGlucoseHela CellsHumanHyperglycemiaIn VitroInsulinInsulin Signaling PathwayKineticsLightMalignant NeoplasmsMessenger RNAMetabolismMethodsMitochondrial ProteinsModificationMolecularMusNuclearNuclear ProteinsNutrientO-GlcNAc transferasePhosphorylationPost-Translational Protein ProcessingProcessProteinsRNARNA Polymerase IIRegulationRoleSignal TransductionSiteSite-Directed MutagenesisStressSurfaceSystemTAF1 geneTATA-Box Binding ProteinTechnologyTherapeuticTimeTissuesTranscription ElongationTranscription InitiationWorkaptamercell typediabetic ratdimerimprovedinsulin signalinglink proteinmetabolomicsnoveloptogeneticspeptide O-linked N-acetylglucosamine-beta-N-acetylglucosaminidasepromoterrecruitresponsescaffoldsensorsugartooltranscriptomics
项目摘要
PROJECT SUMMARY
The cycling of N-acetylglucosamine on Ser(Thr) residues (O-GlcNAcylation; OGN) on nuclear,
cytoplasmic and mitochondrial proteins serves as a nutrient sensor to regulate signaling,
transcription, and cellular physiology. Abnormal OGN underlies the etiology of diabetes, cancer
and Alzheimer's disease. OGN regulates nearly every aspect of transcription in response to
nutrients. Great strides have been made in developing methods that elucidate the functions of
OGN. While we can increase or decrease global OGN in cells, the greatest impediment toward a
mechanistic understanding of OGN's functions is the lack of a method to alter OGN on a single
protein without affecting the other thousands of OGN proteins within a cell.
We discovered that the C-terminal domain of RNA polymerase II, which consists of 52
imperfect repeats of the sequence, YSPTSPS, is heavily OGN when it is not phosphorylated.
OGN of the CTD is required for transcription initiation, is reciprocal with phosphorylation, and the
sugar must be removed by O-GlcNAcase prior to elongation. While there have been many studies
of the role of phosphorylation of the CTD in transcription, in contrast, there have been no studies
of the specific roles of OGN on the CTD!
We propose to develop an optogenetic approach to specifically target the O-GlcNAc
transferase (OGT) to specific proteins. Our plan is to adapt the LOV2 light-inducible dimer (iLID)
system. In this system, light-induced molecular association occurs on the sub-second time scale
and reversion in the dark can occur within ten minutes. Initially, we will use iLID to investigate the
roles of OGN in the insulin signaling pathway. OGT is normally targeted to its substrates by
accessory proteins, among which are TET proteins, enzymes that hydroxymethylate cytosine
residues, but also target OGT to chromatin. We will further investigate the roles of TET proteins
in OGT actions on chromatin, particularly on the CTD of Pol II. Finally, we will study the roles of
OGN on the CTD of RNA pol II in terms of its nutrient and stress responsiveness, and cell type
differences in sites modified. We will elucidate the interactome of OGN-CTD and we will determine
if OGN plays a role in RNA pol II pausing at promoters.
These studies are not only elucidating molecular mechanisms of how nutrients regulate
transcription, but they also are key to revealing how hyperglycemia, as occurs in diabetes,
abnormally alters gene expression in many tissues. Molecular mechanisms revealed in these
studies will likely lead to totally novel targets for the treatment of chronic diseases of aging,
particularly diabetes.
项目摘要
N-乙酰葡糖胺在核上的Ser(Thr)残基上的循环(O-GlcNAc酰化; OGN),
细胞质和线粒体蛋白作为营养传感器来调节信号,
转录和细胞生理学。异常OGN是糖尿病、癌症、糖尿病和糖尿病的病因之一。
和老年痴呆症OGN几乎调节转录的各个方面,
营养素在发展阐明细胞功能的方法方面已经取得了很大的进展,
OGN。虽然我们可以增加或减少细胞中的全局OGN,但最大的障碍是细胞内的OGN。
对OGN功能的机械理解是缺乏一种方法来改变OGN在单个
蛋白质而不影响细胞内其他数千种OGN蛋白质。
我们发现,RNA聚合酶II的C-末端结构域,由52个
序列YSPTSPS的不完全重复在未磷酸化时是重度OGN。
CTD的OGN是转录起始所需的,与磷酸化相互作用,
在延伸之前必须通过O-GlcNAc酶除去糖。虽然有很多研究
CTD磷酸化在转录中的作用,相反,还没有研究
OGN在CTD中的具体作用!
我们建议开发一种光遗传学方法来特异性靶向O-GlcNAc,
转移酶(OGT)与特定蛋白质的结合。我们的计划是将LOV 2光诱导二聚体(iLID)
系统在该体系中,光诱导的分子缔合发生在亚秒级的时间尺度上
并且在黑暗中可以在十分钟内发生逆转。最初,我们将使用iLID来调查
OGN在胰岛素信号通路中的作用。OGT通常通过以下方式靶向其底物:
辅助蛋白质,其中包括泰特蛋白质,即羟甲基化胞嘧啶的酶
残基,而且还将OGT靶向染色质。我们将进一步研究泰特蛋白的作用
在OGT对染色质的作用中,特别是对Pol II的CTD。最后,我们将研究
OGN对RNA pol II CTD的营养和应激反应性以及细胞类型的影响
修改网站的差异。我们将阐明OGN-CTD的相互作用组,并确定
如果OGN在RNA pol II暂停在启动子中起作用。
这些研究不仅阐明了营养素调节的分子机制
转录,但它们也是揭示高血糖症,如糖尿病,
在许多组织中异常地改变基因表达。分子机制揭示了这些
这些研究将可能导致治疗慢性衰老疾病的全新靶点,
尤其是糖尿病。
项目成果
期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Nutrient regulation of the flow of genetic information by O-GlcNAcylation.
- DOI:10.1042/bst20200769
- 发表时间:2021-03
- 期刊:
- 影响因子:3.9
- 作者:Yi Zhu;G. Hart
- 通讯作者:Yi Zhu;G. Hart
Increased O-GlcNAcylation prevents degeneration of dopamine neurons.
- DOI:10.1093/brain/awaa398
- 发表时间:2020-12
- 期刊:
- 影响因子:0
- 作者:G. Hart;Chia‐Wei Huang
- 通讯作者:G. Hart;Chia‐Wei Huang
Potential Roles of O-GlcNAcylation in Primary Cilia- Mediated Energy Metabolism.
- DOI:10.3390/biom10111504
- 发表时间:2020-11-01
- 期刊:
- 影响因子:5.5
- 作者:Tian JL;Gomeshtapeh FI
- 通讯作者:Gomeshtapeh FI
Nutrient regulation of gene expression by O-GlcNAcylation of chromatin.
- DOI:10.1016/j.cbpa.2016.06.005
- 发表时间:2016-08
- 期刊:
- 影响因子:7.8
- 作者:Hardiville, Stephan;Hart, Gerald W.
- 通讯作者:Hart, Gerald W.
The Beginner's Guide to O-GlcNAc: From Nutrient Sensitive Pathway Regulation to Its Impact on the Immune System.
- DOI:10.3389/fimmu.2022.828648
- 发表时间:2022
- 期刊:
- 影响因子:7.3
- 作者:Mannino MP;Hart GW
- 通讯作者:Hart GW
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GERALD Warren HART其他文献
GERALD Warren HART的其他文献
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{{ truncateString('GERALD Warren HART', 18)}}的其他基金
Regulation of Translation by O-GlcNAc - Resubmission 03-05-2020
O-GlcNAc 翻译调节 - 重新提交 03-05-2020
- 批准号:
10308411 - 财政年份:2020
- 资助金额:
$ 28.72万 - 项目类别:
Regulation of Translation by O-GlcNAc - Resubmission 03-05-2020
O-GlcNAc 的翻译调节 - 重新提交 03-05-2020
- 批准号:
10533317 - 财政年份:2020
- 资助金额:
$ 28.72万 - 项目类别:
Nutrient Regulation of Cell Physiology by O-GlcNAcylation
O-GlcNAc 酰化对细胞生理学的营养调节
- 批准号:
10458006 - 财政年份:2016
- 资助金额:
$ 28.72万 - 项目类别:
Nutrient Regulation of Cell Physiology by O-GlcNAcylation
O-GlcNAc 酰化对细胞生理学的营养调节
- 批准号:
10261390 - 财政年份:2016
- 资助金额:
$ 28.72万 - 项目类别:
Nutrient Regulation of Cell Physiology by O-GlcNAcylation
O-GlcNAc 酰化对细胞生理学的营养调节
- 批准号:
9329448 - 财政年份:2016
- 资助金额:
$ 28.72万 - 项目类别:
Nutrient Regulation of Cell Physiology by O-GlcNAcylation
O-GlcNAc 酰化对细胞生理学的营养调节
- 批准号:
9754184 - 财政年份:2016
- 资助金额:
$ 28.72万 - 项目类别:
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