Transcription factors find their targets by reading the epigenetic code. This project aims to elucidate how transcription factors, proteins that regulate gene expression, find their target genes. The hypothesis is that non-DNA binding domains play an essential role in this process. This project expects to transform our understanding of transcription factor families, and how factors in families with the same DNA-binding domain manage to regulate different genes. Expected outcomes of this project ....Transcription factors find their targets by reading the epigenetic code. This project aims to elucidate how transcription factors, proteins that regulate gene expression, find their target genes. The hypothesis is that non-DNA binding domains play an essential role in this process. This project expects to transform our understanding of transcription factor families, and how factors in families with the same DNA-binding domain manage to regulate different genes. Expected outcomes of this project include revealing how accessory proteins help transcription factors identify their targets in the genome by reading epigenetic marks. This should provide significant benefits including improved design of artificial transcription factors to up- or down-regulate specific genes in research and agriculture.Read moreRead less
Designer DNA-binding factors. This project aims to use a natural transcription factor family to enhance the efficiency and functionality of designer DNA-binding factors. Research into the structure and function of zinc finger transcription factors, TAL effectors and CRISPR created designer DNA-binding factors. However, though research has improved the specificity of these factors’ genome-wide binding, their efficacy in regulating the expression of genes requires improvement. Using sequencing, th ....Designer DNA-binding factors. This project aims to use a natural transcription factor family to enhance the efficiency and functionality of designer DNA-binding factors. Research into the structure and function of zinc finger transcription factors, TAL effectors and CRISPR created designer DNA-binding factors. However, though research has improved the specificity of these factors’ genome-wide binding, their efficacy in regulating the expression of genes requires improvement. Using sequencing, the project intends to enhance the efficiency and function of these factors by designing modules to improve the stability of DNA binding and effectiveness in functionally regulating gene expression. The project outcomes could include knowledge enabling the use of genetically engineered DNA-binding proteins to artificially control gene expression, with significant scientific and economic implications.Read moreRead less
Genetic, Cellular and Molecular Analysis of Cardiac Ventricular Septation. The project aims to define the blueprint for ventricular septation in the mammalian heart – how, during heart development, a single ventricle becomes divided in two by a muscular wall, thus creating left and right pumps and electrical circuits serving the body and lung circulations separately. A proprietary mouse genetic model was created and will be used to probe the cellular and molecular mechanisms of septation using n ....Genetic, Cellular and Molecular Analysis of Cardiac Ventricular Septation. The project aims to define the blueprint for ventricular septation in the mammalian heart – how, during heart development, a single ventricle becomes divided in two by a muscular wall, thus creating left and right pumps and electrical circuits serving the body and lung circulations separately. A proprietary mouse genetic model was created and will be used to probe the cellular and molecular mechanisms of septation using new technologies able to resolve biology at a single-cell level. Outcomes may include new knowledge on heart development and evolution, including how the cardiac electrical system is formed, and how cell boundaries and tissue complexity are generated. The project may advance new technologies and create new data resources.Read moreRead less
Old genes learning new tricks: characterising regulatory changes driving increased heart complexity during vertebrate evolution. The heart has dramatically increased in morphological complexity during vertebrate evolution but the molecular basis driving these major changes remains unknown. Using comparative genomics approaches, this project will explore changes in the regulation of genes involved in heart formation that lead to changes in cardiac structure. It will elucidate for the first time t ....Old genes learning new tricks: characterising regulatory changes driving increased heart complexity during vertebrate evolution. The heart has dramatically increased in morphological complexity during vertebrate evolution but the molecular basis driving these major changes remains unknown. Using comparative genomics approaches, this project will explore changes in the regulation of genes involved in heart formation that lead to changes in cardiac structure. It will elucidate for the first time the cardiac regulatory repertoire in zebrafish and will compare it with that of fly and mouse using cutting-edge bioinformatics pipelines. This work will unravel cardiac-specific regulatory modifications that give rise to evolutionary changes. On a broader scale, it will shed new light on the role of regulatory innovations over gene innovations in the emergence of new traits.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
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
Kruppel-like factors and the methylome. This project aims to test the hypothesis that the KLF/SP family of transcription factors work in part via dynamic interactions with methylated cytosine nucleotides in DNA. This is fundamental to their function as pioneer factors in reprograming and their ability to co-ordinate differentiation and organogenesis. Conversely, dynamic changes in methylation status engage or disengage new regulatory elements in the genome via recruitment of KLF/SP family protei ....Kruppel-like factors and the methylome. This project aims to test the hypothesis that the KLF/SP family of transcription factors work in part via dynamic interactions with methylated cytosine nucleotides in DNA. This is fundamental to their function as pioneer factors in reprograming and their ability to co-ordinate differentiation and organogenesis. Conversely, dynamic changes in methylation status engage or disengage new regulatory elements in the genome via recruitment of KLF/SP family proteins as specific effectors. This project will address a new paradigm in genetics that is likely to underpin development.Read moreRead less
Sex determination in dragons: Genetics, epigenetics and environment. This project aims to discover the master sex-determining gene in a reptile, how that gene is differentially regulated in males and females and by temperature, and to identify evolutionary drivers of transitions between genetic and environmental sex determination. In many reptiles, like mammals, chromosomes determine sex. In others, the temperature at which their eggs are incubated determines sex. This project will study how tem ....Sex determination in dragons: Genetics, epigenetics and environment. This project aims to discover the master sex-determining gene in a reptile, how that gene is differentially regulated in males and females and by temperature, and to identify evolutionary drivers of transitions between genetic and environmental sex determination. In many reptiles, like mammals, chromosomes determine sex. In others, the temperature at which their eggs are incubated determines sex. This project will study how temperature reverses chromosomal sex determination in dragon lizards. This could show how climatic extremes affect the biology of climate sensitive reptiles, and understand their vulnerability to climate change.Read moreRead less
Uniting histone and transcription factor codes. This project aims to establish the general features of the “histone code”. It is well established that gene expression patterns are determined in part by the deposition, recognition and removal of post-translational modifications on the histone proteins that package eukaryotic DNA. This project proposes that this "histone code" is in fact a specific example of a transcription factor code. The project aims to enhance our understanding of the mechani ....Uniting histone and transcription factor codes. This project aims to establish the general features of the “histone code”. It is well established that gene expression patterns are determined in part by the deposition, recognition and removal of post-translational modifications on the histone proteins that package eukaryotic DNA. This project proposes that this "histone code" is in fact a specific example of a transcription factor code. The project aims to enhance our understanding of the mechanisms underlying gene regulation in plants and animals, and help to create improved strategies to optimise crop and farm animal properties and new-generation therapeutics.Read moreRead less
Investigating a new way in which diet impacts animal biology. This project aims to investigate the importance of a new way in which diet can alter animal biology. High fat or high sugar diets increase the binding of products of metabolism to chromosomes, which can completely alter the way that DNA is packaged and read. This project will use cell culture, rodent and fly models to identify the regions of the genome that are most affected by the new process. The project will also determine whether ....Investigating a new way in which diet impacts animal biology. This project aims to investigate the importance of a new way in which diet can alter animal biology. High fat or high sugar diets increase the binding of products of metabolism to chromosomes, which can completely alter the way that DNA is packaged and read. This project will use cell culture, rodent and fly models to identify the regions of the genome that are most affected by the new process. The project will also determine whether the cell is harmed, or in fact harnesses the process to control development or metabolism. This project has implications for our understanding of the ways in which genes interact with the environment especially in times of change.Read moreRead less