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

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.

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.

There is widespread interest in the transcriptional gene silencing (TGS) in human cells. However, very little is understood about the exact mechanism. The understanding of the properties of TGS in human cells is quickly outstripping the very limited amount that is known about induced gene expression regulation on transcriptional level. This project would therefore have an impact not only in biological fields, but also potentially in fields such as nanotechnology and biotechnology.
The project would open up fundamentally novel questions about TGS mechanism, and will therefore not only determine the role of TGS in gene regulation, but will also be relevant to development of a new research tool. This research proposal may be particularly interesting for scientific community, not only because of providing a new knowledge, but also for potential use of CT as a new tool for knocking down genes on transcriptional level in mammalian cells. There are no efficient commercially available tools for switching off the genes on transcriptional level at the moment.
The idea of CT induced TGS in human cells has been filed as patent by Isis Innovations at Oxford University and was received with great interest from various biotech companies. This project will help to develop a range of useful tools for scientific community as well as new therapeutic agents, which will be of great benefic for general public.