Adaptive reprogramming of metabolism in regeneration. . Biologists have long been intrigued at the phenomenon of organ regeneration. Unlike most human organs, the liver exhibits the remarkable capacity to regenerate. Despite decades of research, the molecular underpinnings of liver regeneration are poorly understood. This research proposal aims to use zebrafish to elucidate the pathways involved in sensing injury and activating an adaptive transcriptional and metabolic response to orchestrate re ....Adaptive reprogramming of metabolism in regeneration. . Biologists have long been intrigued at the phenomenon of organ regeneration. Unlike most human organs, the liver exhibits the remarkable capacity to regenerate. Despite decades of research, the molecular underpinnings of liver regeneration are poorly understood. This research proposal aims to use zebrafish to elucidate the pathways involved in sensing injury and activating an adaptive transcriptional and metabolic response to orchestrate regeneration. Ultimately, this works aims to understand the metabolic requirements for regeneration. Expected outcomes include scholarly publications revealing fundamental principles of regeneration, new resources and pipelines for the research community as well as training for research students.Read moreRead less
Investigating non-canonical RNA processing in developing spermatids. RNA combines the information content of DNA and the physical properties of proteins. These features mean it's emerging as a major player for new knowledge; for answers to fundamental questions in biology, and for applications in biotechnology. This project aims to understand how non-canonical RNA processing events control gene expression. How mRNA is processed post-transcriptionally for selective storage, translation, stabilisa ....Investigating non-canonical RNA processing in developing spermatids. RNA combines the information content of DNA and the physical properties of proteins. These features mean it's emerging as a major player for new knowledge; for answers to fundamental questions in biology, and for applications in biotechnology. This project aims to understand how non-canonical RNA processing events control gene expression. How mRNA is processed post-transcriptionally for selective storage, translation, stabilisation or decay to control development. RNA-driven processes program morphogenesis and differentiation of spermatids, but via mechanisms only poorly understood. Uncovering the function of extensive cytoplasmic polyadenylation, which is essential for murine fertility, may fuel the next wave of RNA biotech applications. Read moreRead less
Understanding co-activator function in transcriptional regulation. A change in gene expression underpins all cell fate decisions yet there is scant knowledge about how transcription factors (TF), the master regulators of transcription, specifically interact with some, but not all, transcription cofactors to nuance gene expression. Aims: Using innovative molecular technologies we will identify and characterise the shared and unique relationships between TF and cofactors. Significance: This study ....Understanding co-activator function in transcriptional regulation. A change in gene expression underpins all cell fate decisions yet there is scant knowledge about how transcription factors (TF), the master regulators of transcription, specifically interact with some, but not all, transcription cofactors to nuance gene expression. Aims: Using innovative molecular technologies we will identify and characterise the shared and unique relationships between TF and cofactors. Significance: This study is important to every biological process in plants and animals driven by a change in gene expression. Expected Outcomes: This study will increase our biological knowledge in transcription control. Benefit: The knowledge gained has future applications in genomics and broad implications for biotechnology and industry.Read moreRead less
Can we exploit mRNA modifications to control protein expression? Genes are encoded by DNA but are transcribed into a message called RNA before they can be translated into protein. RNA can be chemically modified at a gene-specific level, and this modification has been central to the success of RNA vaccines against COVID-19. Despite the importance of these modifications in cellular life and in biotechnology, the role of the most abundant RNA modifications is unclear. This project will investigate ....Can we exploit mRNA modifications to control protein expression? Genes are encoded by DNA but are transcribed into a message called RNA before they can be translated into protein. RNA can be chemically modified at a gene-specific level, and this modification has been central to the success of RNA vaccines against COVID-19. Despite the importance of these modifications in cellular life and in biotechnology, the role of the most abundant RNA modifications is unclear. This project will investigate how we can exploit RNA modifications to modulate protein expression in a tractable single-celled organism with a small genome, Plasmodium. This information is important because understanding gene regulation is fundamental to all life, and the role of RNA modifications is emerging as integral to biotechnology.Read moreRead less
Genetic variation of single cell transcriptional heterogeneity in HiPSCs. This project aims to investigate whether induced pluripotent stem cells (iPSC) can be used to study the functions of genetic variants associated with human phenotypes and cell fate decisions. The project will utilise technology to produce single cell RNA sequence data for 100,000s of cells. By sequencing individual cells, the genetic control of cellular heterogeneity both within and between cells can be identified, and in ....Genetic variation of single cell transcriptional heterogeneity in HiPSCs. This project aims to investigate whether induced pluripotent stem cells (iPSC) can be used to study the functions of genetic variants associated with human phenotypes and cell fate decisions. The project will utilise technology to produce single cell RNA sequence data for 100,000s of cells. By sequencing individual cells, the genetic control of cellular heterogeneity both within and between cells can be identified, and in doing so, will provide significant benefit by revealing the potential for iPSC to be used for functional translation of human genomics.Read moreRead less
Protein Kinase Regulatory Switches: Decision-Making in the Nucleus. This project plans to examine new regulatory mechanisms for an important signalling enzyme in the cell nucleus. It aims to define how this enzyme enters the nucleus, to characterise new modifications that affect its actions, and to establish how a conserved nuclear protein may provide an unexpected regulatory platform to send nucleus-initiated signals back to the cell cytoplasm. This reverse signalling is a novel mechanism for i ....Protein Kinase Regulatory Switches: Decision-Making in the Nucleus. This project plans to examine new regulatory mechanisms for an important signalling enzyme in the cell nucleus. It aims to define how this enzyme enters the nucleus, to characterise new modifications that affect its actions, and to establish how a conserved nuclear protein may provide an unexpected regulatory platform to send nucleus-initiated signals back to the cell cytoplasm. This reverse signalling is a novel mechanism for integrating nuclear actions that has the potential to create a signal transduction circuit triggered by environmental or genetic factors. This information is crucial in defining the molecular logic of signalling events that may be ultimately targeted to control cell growth, differentiation and survival.Read moreRead less
How to build the head: A molecular mechanistic insight. This project aims to gain an insight into the functional output of the gene regulatory network and the molecular determinants that are critical for the formation of the head. Genome-wide sequencing technologies are employed to identify the ensemble of genes that are regulated by Lhx1. By a combination of bioinformatics analysis and a system biology approach, the project aims to build a model of the network of the interacting genes for head ....How to build the head: A molecular mechanistic insight. This project aims to gain an insight into the functional output of the gene regulatory network and the molecular determinants that are critical for the formation of the head. Genome-wide sequencing technologies are employed to identify the ensemble of genes that are regulated by Lhx1. By a combination of bioinformatics analysis and a system biology approach, the project aims to build a model of the network of the interacting genes for head development, and to characterise the function of selected components of this network to refine its architecture and define the dynamics of the network. The knowledge may improve our understanding of the molecular mechanism underpinning the naturally-occurring variation in the forms of major body parts, and of how genes and signals work cooperatively to build an embryo.Read moreRead less
3'UTR switching in eukaryotic cells. The project aims to uncover conserved features fundamental to the mechanism and function of post-transcriptional gene-expression control. RNA systems interface the executive functions of DNA and the worker functions of proteins. mRNA often dictates the level, timing and location of protein synthesis. This project will use RNA-sequencing and bespoke bioinformatics to probe global RNA-dynamics. Mixing yeast-genetics with RNA-technologies, it focuses on 3’ untra ....3'UTR switching in eukaryotic cells. The project aims to uncover conserved features fundamental to the mechanism and function of post-transcriptional gene-expression control. RNA systems interface the executive functions of DNA and the worker functions of proteins. mRNA often dictates the level, timing and location of protein synthesis. This project will use RNA-sequencing and bespoke bioinformatics to probe global RNA-dynamics. Mixing yeast-genetics with RNA-technologies, it focuses on 3’ untranslated region (UTR) dynamics in eukaryotic cell biology. This project expects to significantly advance the understanding of eukaryotic gene function and gene regulation, critical in an age of personalised genomic medicine.Read moreRead less
Investigating Hippo-regulated transcription at single molecule resolution. Signalling pathways operate throughout life to relay signals from the extracellular world to the cellular nucleus, to control transcription and elicit a response. This project aims to understand how the Hippo growth control pathway regulates transcription. Using a combination of biology, biophysics and computational biology, this project aims to quantify behaviour of the Hippo pathway transcription factors at sub-micron r ....Investigating Hippo-regulated transcription at single molecule resolution. Signalling pathways operate throughout life to relay signals from the extracellular world to the cellular nucleus, to control transcription and elicit a response. This project aims to understand how the Hippo growth control pathway regulates transcription. Using a combination of biology, biophysics and computational biology, this project aims to quantify behaviour of the Hippo pathway transcription factors at sub-micron resolution, and how Hippo signalling modulates their behaviour, interaction with the genome and function. We anticipate our discoveries will stimulate new research, e.g. testing of how other signaling pathways regulate transcription. Intended benefits are creation of jobs and new knowledge on fundamental principles of life.Read moreRead less
Photoreversible hydrogels to study stem cell memory and fate. This project will develop materials whose stiffness can be reversibly increased and decreased by the simple application of light, and use these to build knowledge of how stem cell fate is regulated. The influence of mechanical cues on the structure and organisation of the nucleus will be determined. Expected outcomes are new synthetic and light-reversible culture materials, and fundamental insights into how forces change the nucleus t ....Photoreversible hydrogels to study stem cell memory and fate. This project will develop materials whose stiffness can be reversibly increased and decreased by the simple application of light, and use these to build knowledge of how stem cell fate is regulated. The influence of mechanical cues on the structure and organisation of the nucleus will be determined. Expected outcomes are new synthetic and light-reversible culture materials, and fundamental insights into how forces change the nucleus to alter stem cell aging and fate. The findings will provide critical information required for the future development of assays to measure cell potency and instructive biomaterials to drive stem cell expansion and tissue-regeneration and will have impact by underpinning future advances in stem cell technologies.Read moreRead less