Mechanism of transcriptional gene silencing induced by convergent transcription in human cells and its application in breast cancer.

人类细胞中聚合转录诱导的转录基因沉默机制及其在乳腺癌中的应用。

• 批准号: MR/K006606/1
• 负责人: Monika Gullerova
• 金额: $ 125.29万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK006606%2F1
• 关键词: Mechanism; transcriptional; gene; silencing; induced

All organisms consist of cells that multiply through cell division. The genetic code, which defines each cell type, is stored within DNA molecules. DNA contains coding regions called genes. Genes are transcribed into messenger RNA (mRNA) molecules, which are in turn translated into proteins, a process called gene expression. It is important that each cell makes the right levels of proteins, which is achieved by controlled gene expression. Uncontrolled gene expression can lead to cancer or cell death. One of the most important mechanisms for the regulation of gene expression is gene silencing. Gene silencing in human cells requires the presence of small RNA molecules (siRNA), which activate the RNAi pathway. This leads to recognition and distruction of target mRNA in the cytoplasm. Another type of gene silencing is the establishment of specific modifications on DNA, which leads to inhibition of gene transcription, also called transcriptional gene silencing (TGS). Little is understood about the mechanism of TGS in humans. The work proposed in this fellowship application will use available knowledge about TGS from other organisms to investigate and explore the details of how TGS can be induced in humans and by what mechanism. This work has important implications given that it can lead to development of new research tools with a great potential for therapeutic application.

所有生物体都是由通过细胞分裂繁殖的细胞组成的。定义每种细胞类型的遗传密码存储在DNA分子中。DNA包含称为基因的编码区。基因被转录成信使RNA（mRNA）分子，后者又被翻译成蛋白质，这一过程称为基因表达。重要的是，每个细胞都能产生正确水平的蛋白质，这是通过控制基因表达来实现的。不受控制的基因表达可能导致癌症或细胞死亡。基因沉默是基因表达调控的重要机制之一。人类细胞中的基因沉默需要小RNA分子（siRNA）的存在，其激活RNAi途径。这导致细胞质中靶mRNA的识别和破坏。另一种类型的基因沉默是在DNA上建立特异性修饰，这导致基因转录的抑制，也称为转录基因沉默（TGS）。关于TGS在人类中的机制知之甚少。这项奖学金申请中提出的工作将利用其他生物体关于TGS的现有知识，调查和探索TGS如何在人类中诱导以及通过何种机制诱导的细节。这项工作具有重要的意义，因为它可以导致开发新的研究工具，具有巨大的治疗应用潜力。

项目成果

Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation.

• DOI: 10.1101/gr.193995.115
• 发表时间: 2016-01
• 期刊: Genome research
• 影响因子: 7
• 作者: Neve J;Burger K;Li W;Hoque M;Patel R;Tian B;Gullerova M;Furger A
• 通讯作者: Furger A

Nuclear re-localization of Dicer in primary mouse embryonic fibroblast nuclei following DNA damage.

• DOI: 10.1371/journal.pgen.1007151
• 发表时间: 2018-03
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Burger K;Gullerova M
• 通讯作者: Gullerova M

p19-mediated enrichment and detection of siRNAs.

p19 介导的 siRNA 富集和检测。

• DOI: 10.1007/978-1-4939-0931-5_9
• 发表时间: 2014
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Jin J

Genome-wide analysis of poly(A) site selection in Schizosaccharomyces pombe.

• DOI: 10.1261/rna.040675.113
• 发表时间: 2013-12
• 期刊: RNA (New York, N.Y.)
• 作者: Schlackow M;Marguerat S;Proudfoot NJ;Bähler J;Erban R;Gullerova M
• 通讯作者: Gullerova M

Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA.

• DOI: 10.1038/nsmb.2827
• 发表时间: 2014-06
• 期刊: Nature structural & molecular biology
• 影响因子: 16.8
• 作者: White E;Schlackow M;Kamieniarz-Gdula K;Proudfoot NJ;Gullerova M
• 通讯作者: Gullerova M