Role of m6A RNA methylation in Regulation of Translation in Human Glioblastoma
m6A RNA 甲基化在人胶质母细胞瘤翻译调节中的作用
基本信息
- 批准号:9982242
- 负责人:
- 金额:$ 17.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-23 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAggressive behaviorBindingBiologicalBiological AssayCell Differentiation processCellsComputer AnalysisDataEctopic ExpressionEpigenetic ProcessEquilibriumGenetic studyGlioblastomaGliomaGoalsHumanImmunoprecipitationInformal Social ControlKnowledgeMaintenanceMalignant NeoplasmsMalignant neoplasm of brainMediatingMethyltransferaseMicroRNAsMolecularNuclearPatientsPatternPrimary Brain NeoplasmsProcessPublicationsRNARNA methylationRecurrenceRegulationRoleSamplingSeedsTherapeutic InterventionTimeTranscriptTranslationsTreatment FailureTumorigenicitycancer cellepitranscriptomeinsightnew therapeutic targetnoveloutcome forecastribosome profilingself-renewalstem cell differentiationstem cellstargeted treatmenttranscriptome sequencingtumortumor growthtumor heterogeneity
项目摘要
Abstract
Glioblastoma represents the most aggressive type of human brain cancer with dismal prognosis. Recent
studies have revealed extensive intratumoral heterogeneity in transcript expression and increased plasticity of
human glioma stem cells, which are thought to contribute to treatment failure and tumor recurrence. The role of
m6A RNA and ALKBH5 in the regulation of self-renewal and maintenance of tumorigenicity of glioma stem cells
has been recently demonstrated. Limited knowledge exists with regards to the role of m6A RNA methylation in
the regulation of translation efficiency in human cancer cells. Moreover, the role of m6A RNA methylation
machinery that includes m6A “writers” (methyltransferases e.g. Mettl14, Mettl3) and “erasers” (demethylases
e.g. ALKBH5, FTO), in the regulation of translation during the transition of human glioma stem cells to
differentiated glioma cells has not been studied.
We hypothesize that alterations at the level of m6A RNA methylation influences the rate of translation of certain
transcripts during the transition of human glioma stem cells to differentiated cells. We propose that loss of m6A
RNA methylation increases the rate of translation of transcripts with sequence motifs of their m6A peak regions
that are complementary to the seed sequences of specific miRNAs. These miRNAs interact and regulate the
m6A RNA machinery in human glioma cells.
The specific aims of our proposal will provide a comprehensive and subtype specific insight into the role of m6A
RNA in the regulation of translation during the transition between hGSCs and differentiated GCs:
-SA1: Perform RNA sequencing, MeRIP sequencing, Ribo-sequencing and computational analysis of 10
additional human glioma stem cells and differentiated glioma cells
-SA2: Determine the functional significance of the miRNA binding within the m6A RNA methylation peaks and
how the miRNAs regulate RNA methylation machinery.
Our proposal constitutes a functional exploration of the role of m6A RNA methylation in the regulation of
translation during the transition of hGSCs to differentiated cells. In addition, it introduces the role of specific
miRNAs as regulators of hGSC translation through modulation of the RNA methylation machinery. Since the
reversible transition of hGSCs to differentiated cells constitutes a critical denominator of tumor recurrence and
aggression, identification of molecular regulators of this process could provide novel targets for therapeutic
interventions.
摘要
胶质母细胞瘤是最具侵袭性的人类脑癌类型,预后不良。最近
研究揭示了肿瘤内转录表达的广泛异质性和肿瘤细胞的可塑性增加,
人类神经胶质瘤干细胞,这被认为有助于治疗失败和肿瘤复发。的作用
m6 A RNA和ALKBH 5对胶质瘤干细胞自我更新和致瘤性维持的调控
最近得到了证实。关于m6 A RNA甲基化在细胞凋亡中的作用,
人类癌细胞翻译效率的调节。此外,m6 A RNA甲基化的作用
包括m6 A“写入器”(甲基转移酶,例如Mettl 14、Mettl 3)和“擦除器”(脱甲基酶)的机器
例如ALKBH 5,FTO),在人脑胶质瘤干细胞向神经胶质瘤干细胞转化过程中的翻译调节中起作用。
尚未研究分化的神经胶质瘤细胞。
我们假设m6 A RNA甲基化水平的改变会影响某些转录因子的翻译速率。
在人胶质瘤干细胞向分化细胞的转变过程中转录。我们认为m6 A的缺失
RNA甲基化增加具有m6 A峰区域序列基序的转录物的翻译速率
与特定miRNAs的种子序列互补。这些miRNAs相互作用并调节
人神经胶质瘤细胞中的m6 A RNA机器。
我们提案的具体目标将为m6 A的作用提供全面和亚型特异性的见解
RNA在hGSC和分化的GC之间的转变期间调节翻译:
- SA 1:进行RNA测序、MeRIP测序、核糖核酸测序和10个核苷酸的计算分析
另外的人胶质瘤干细胞和分化的胶质瘤细胞
- SA 2:确定m6 A RNA甲基化峰内的miRNA结合的功能意义,以及
miRNAs如何调节RNA甲基化机制。
我们的建议构成了m6 A RNA甲基化在调节细胞凋亡中的作用的功能探索。
在hGSC向分化细胞的转变过程中的翻译。此外,还介绍了具体的
miRNA通过调节RNA甲基化机制作为hGSC翻译的调节剂。以来
hGSC向分化细胞的可逆转变构成了肿瘤复发的关键因素,
因此,鉴定这一过程的分子调节剂可以为治疗提供新的靶点。
干预措施。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Advances in Lipid-Based Nanoparticles for Cancer Chemoimmunotherapy.
- DOI:10.3390/pharmaceutics13040520
- 发表时间:2021-04-09
- 期刊:
- 影响因子:5.4
- 作者:Wang T;Suita Y;Miriyala S;Dean J;Tapinos N;Shen J
- 通讯作者:Shen J
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{{ truncateString('Nikolaos Tapinos', 18)}}的其他基金
Role of an alternatively spliced nuclear variant of ErbB3 in the nervous system
ErbB3 的选择性剪接核变体在神经系统中的作用
- 批准号:
8071111 - 财政年份:2010
- 资助金额:
$ 17.67万 - 项目类别:
Role of an alternatively spliced nuclear variant of ErbB3 in the nervous system
ErbB3 的选择性剪接核变体在神经系统中的作用
- 批准号:
8462307 - 财政年份:2010
- 资助金额:
$ 17.67万 - 项目类别:
Role of an alternatively spliced nuclear variant of ErbB3 in the nervous system
ErbB3 的选择性剪接核变体在神经系统中的作用
- 批准号:
7947834 - 财政年份:2010
- 资助金额:
$ 17.67万 - 项目类别:
Role of an alternatively spliced nuclear variant of ErbB3 in the nervous system
ErbB3 的选择性剪接核变体在神经系统中的作用
- 批准号:
8258765 - 财政年份:2010
- 资助金额:
$ 17.67万 - 项目类别:
Role of an alternatively spliced nuclear variant of ErbB3 in the nervous system
ErbB3 的选择性剪接核变体在神经系统中的作用
- 批准号:
8643827 - 财政年份:2010
- 资助金额:
$ 17.67万 - 项目类别:
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