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KAUST PhD Studentship

4-year PhD Studentships in Genetics

Department of Genetics has 4-year PhD studentships supported by the KAUST Fund for Biological Sciences and the Cambridge Biosciences Doctoral Training Programme that are being offered for the projects outlined below. The studentship will cover the fees (at Home/EU rate) and an annual stipend at RCUK rates.

Potential applicants are strongly advised to make an informal approach to the relevant Supervisor before applying via the University Graduate application system https://www.graduate.study.cam.ac.uk

The deadline for applications is Friday 29th January 2021. 

Those applicants who also wish to be considered for Cambridge Trust funding through the University Scholarship competitions must have applications submitted by Thursday 7thJanuary 2021

Projects

 

Using single cell analyses to determine the transcriptional and chromatin regulatory events underlying development

Prof Julie Ahringer

http://www.ahringer.group.gurdon.cam.ac.uk/

ja219@cam.ac.uk

 

Animal development is an extraordinary process during which a single-celled totipotent zygote produces a multitude of different tissues and cell types. The zygotic genome is activated following initial quiescence, cells undergo lineage selection and refinement, and eventually committed cells engage in differentiation programmes. The mechanisms that drive these transitions are poorly understood. Single cell profiling of embryos of some animals has uncovered dynamic changes in transcription and chromatin. However, the complexity of most systems makes it impossible at present to determine the genome regulatory changes between mother and daughter cells. This problem is solved in C. elegans because the lineal relationship and location of every cell is invariant and known. This exceptional property makes it feasible to determine the locus-specific regulation of chromatin and gene expression at every cell division from the zygote to the differentiated state, by mapping single cell data onto the lineage tree. This PhD project will use single-cell profiling to determine the progression of genomic regulation through a specific developmental process (e.g., zygotic genome activation, lineage commitment, or organ development) and the mechanisms of key transitions through study of mutants. This will reveal principles by which the genome directs development and impact understanding of diseases that result from chromatin dysregulation.

 

Epigenetic control of the mammary gland cycle

Prof Anne Ferguson-Smith

http://www.gen.cam.ac.uk/research-groups/ferguson-smith

afsmith@gen.cam.ac.uk

 

The mammary gland evolved over 300 million years ago to provide nutrition to the neonate. It is capable of rapid complex development to produce milk during lactation, followed by remodelling and apoptosis upon weaning. The cycle re-initiates with the next and subsequent pregnancies.

 

Our group studies mammalian epigenetic inheritance the epigenetic control of genome function. In a separate programme designed to understand the contribution of genomic imprinting to postnatal resource control, we have created a robust, novel and unique dataset of transcriptomes from the mouse mammary gland. This high resolution dataset of 480 transcriptomes, is generated from 6 cell types from 10 different time points in the mammary gland cycle providing a comprehensive timeline for the virgin mammary gland and early, middle and late time points during gestation, lactation and involution.

 

In this proposed project, the student will address the dynamic epigenetic control of the mammary gland cycle by complementing these transcriptomes with base-resolution methylomes, ATAC-seq datasets for chromatin states, and histone modification data. They will generate these datasets and carry out extensive bioinformatic and data analysis and integration pipelines. These studies will consider the extent to which epigenetic states establish and/or maintain particular regulatory contexts during the mammary gland cycle, and provide novel insights into cyclical regulation that can be considered alongside the more established longitudinal epigenetic changes that occur during development. Results will have implications for our understanding of a unique developmental niche that plays a critical role in maternal-offspring resource allocation and the future health and wellbeing of offspring.

 

Germline biology

Dr Felipe Karam Teixeira

https://karamteixeira.wixsite.com/website

fk319@cam.ac.uk

 

1) Protein synthesis regulation controlling stem cell self-renewal and differentiation:

Accumulating evidence indicate that regulation of protein synthesis plays critical roles during development, tissue homeostasis, and tumorigenesis (Teixeira and Lehmann, CSH Persp 2019). Yet, the study of spatiotemporal regulation of gene expression and its function in controlling stem cells has been mostly restricted to chromatin-based mechanisms. We have previously shown that translation is actively regulated during fate transitions and that this is critically required for stem cell self-renewal and differentiation in vivo (Sanchez et al, Cell Stem Cell 2016). Using genetics, biochemistry, microscopy, and high-throughput sequencing analyses (small RNA-seq, RNA-seq, Ribo-seq), we aim to build a refined molecular understanding of how protein synthesis control – a new frontier in gene regulation – governs key aspects of stem cell biology in vitro and in vivo.

 

2) Mechanisms safeguarding genome integrity during germline development:

Accumulation of unrepaired damage in the germline can lead to infertility and tumor development. The major threat to the germline genome is provided by selfish DNA modules known as transposons – mobile units that compose a large fraction of our genomes and that aim to increase in copy number by mobilization. Exploiting classic genetics tools in flies (Ghanim et al, Open Biol 2020; Teixeira et al, Nature 2017), we aim to understand, at the single-cell level, how germ cells assess, control, and respond to transposon activity during development. Current projects involve developmental, microscopy, and next-generation sequencing in combination with transgenic reporters and FACS sorting to study how molecular checkpoints operate in germ cells during development.

 

3) Small RNA- and chromatin-mediated regulation of alternative splicing:

Transposable elements can drive genome evolution, but their enhanced activity is detrimental to the host and must be regulated. We have recently uncovered a novel mechanism by which an evolutionary conserved small RNA machinery (known as the piRNA pathway) controls transposon activity by regulating chromatin states and alternative splicing (Teixeira et al, Nature 2017). Building on this, current projects aim to dissect the emerging and exciting relationship between chromatin states, transcription, and splicing regulation in vivo. This is being achieved by combining genetics (using nuclease deficient Cas9 (dCas9) protein fusions), biochemical (Mass Spec), and genomic (ChIP-seq and qPCR) approaches.

 

Engineering protein glycosylation

Prof Gos Micklem

http://www.micklemlab.org

gm263@cam.ac.uk

 

The humanisation of protein glycosylation in different organisms for the production of therapeutic glycoproteins including antibodies, has been the subject of much research and multiple engineering attempts. Protein glycosylation is a complex non-templated process involving tens of enzymes and hundreds of genes in mammalian cells and thus engineering attempts are still far from achieving a model system suitable for the production of all therapeutic human glycoproteins. Currently it is necessary to use mammalian cell tissue culture, which is slow, expensive and prone to viral and other infections, pushing up the cost of antibody-based therapies. Thus opportunities remain to create lower eukaryotic systems that can carry out human glycosylation correctly but that can also grow rapidly on cheap feedstocks

 

This project builds on a pilot design that identified the key genes and pathways involved in glycosylation in yeast and human and outlined a way to modify/assemble them progressively. The project centres around a novel approach to the humanisation of glycosylation in yeast, utilising the latest synthetic biology and systems approaches including SCRaMbLE, synthetic chromosome design and assembly, and high throughput screening and analysis.

 

An understanding of protein glycosylation, and synthetic biology techniques including methods like Gibson assembly and the start-stop variant of Golden Gate assembly would be valuable. Screening methods including lectin based assays and mass-spectrometry will be important in this project. The engineering process including systematic analysis of output strains, ability to evaluate the design, screening process, and workflow, and make phased improvement will play an important role in the success of this project.

 

Endoplasmic reticulum neuronal disease models

Dr Cahir O'Kane

https://www.gen.cam.ac.uk/research-groups/research-groups/okane

cahiro@gmail.com      

 

Axons contain a continuous network of tubular smooth endoplasmic reticulum (ER), with striking specialisations. Its length and physical continuity make it a potential channel for long-range signaling, like a "neuron-within-a-neuron". Axonal ER also has a tiny lumen, sometimes not even visible by EM, which could limit both its ability to buffer Ca2+, and diffusion of lumen contents. The reasons for this specialised architecture are not clear, but mutations in some of the genes whose products shape axonal ER, cause the axon degeneration disease, Hereditary Spastic Paraplegia (HSP). Using Drosophila, we have shown that wildtype axonal ER is a dynamic network, we generated mutants in HSP genes, and used confocal and electron microscopy to show that these mutations can both impair ER continuity and lead to an enlarged lumen. Photobleaching experiments also suggest that the tiny lumen diameter is a constraint on protein diffusion in the lumen.                                                                                                                                                                                                                                                                                                          Our lab has three main goals:  to understand (1) the processes that regulate formation of axonal ER and its specialised architecture, and (2) the role of this architecture and its biophysical properties in the physiological functions of axonal ER, and (3) the pathological consequences of disrupting axonal ER architecture.

For further background about our work:

https://elifesciences.org/articles/23882

https://www.frontiersin.org/articles/10.3389/fnins.2020.00048

 

 

Investigating how microtubules are organised in epithelial cells.

Prof Daniel St Johnston

https://www.gurdon.cam.ac.uk/research/stjohnston

ds139@cam.ac.uk  

 

The establishment and maintenance of apical-basal polarity is essential for both the formation and function of epithelia, whereas a loss of this polarity is a hallmark of carcinomas.  A key step in the polarisation of epithelial cells is the formation of apical-basal arrays of microtubules that are nucleated from apical, noncentrosomal microtubule organising centres (ncMTOCs). Almost nothing is known, however, about how cortical polarity proteins recruit ncMTOCs to the apical side or the composition and the mechanisms of action of these ncMTOCs. The proposed PhD project will use modern proximity labelling techniques (using TurboID and Apex2) to identify novel components of the ncMTOCs and their binding partners and will analyse how these factors are regulated by apical and lateral polarity kinases, using genetics, genome modification by CRISPR-Cas9/Prime editing and the state of art fluorescence microscopy using Drosophila follicle cells as a model epithelial tissue.

 

Understanding and engineering the interplay of cell movement and signalling during intermediate mesoderm speculation.

Dr Ben Steventon

Website: https://steventonlab.wordpress.com/ 

email: bjs57@cam.ac.uk 

The vertebrate body plan is established during gastrulation. This is a highly complex process that consists of a series of well-coordinated cell movements that together generate distinct tissue germ layers and also begin the process of embryo elongation and tissue shaping. At the same time, a series of inter-tissue inductive events act to relay signals between cell populations that in doing so increase in their complexity of specified cell types as gene-regulatory networks act within cells to define them. Up until now, these two aspects of gastrulation, i.e. the cell movements leading to morphogenesis, and the gene regulatory events leading to cell specification, have been studied in isolation from one another. A complete understanding of how these processes are integrated during early development would enable us to take an engineering approach in the generation of specific cell types and tissues structures in vitro.

The aim of this project is to achieve targeted differentiation of intermediate mesoderm (IM) derivatives within self-organising aggregates of embryonic stem cells, or gastruloids. Firstly, we will take a reverse-engineering approach to discover a gene-regulatory network capable of predicting mesodermal specification trajectories in mouse gastrulation. This involves a novel ‘live modelling’ approach involving simulating the output of mathematical models of cell specification on top of 3D cell tracking data from the whole embryo. Secondly, we will ask whether the same network that enables the prediction of mesodermal specification in mouse embryos can also recapitulate the patterning events observed in gastruloids cultured in vitro. Finally, we will engineer the gastruloid protocol to increase the proportion of IM progenitors present and to recapitulate the anterior-posterior patterning and elongation events known to occur in vivo.

 

Genome Biology of Drosophila Sox Transcription Factors

Prof Steve Russell

https://www.gen.cam.ac.uk/research-groups/research-groups/russell

s.russell@gen.cam.ac.uk

 

Sox domain transcriptions factors are highly conserved metazoan developmental regulators with critical roles in stem cell biology and nervous system specification amongst others. We use the Drosophila model system to understand key aspects of Sox protein function using genome biology and genetic approaches. An interesting facet of Sox biology is the apparent functional redundancy shown by related members of the same Sox subgroup and we are interested in understanding the molecular basis of this. We are also interested in understanding the extent to which Sox proteins are functionally conserved across evolution, with our current evidence indicating a complex functional relationship between fly and mammalian orthologues. Projects built around these questions will involve genomics, genetics, developmental biology and bioinformatics.

 

Arefin B., et al (2019). Drosophila Neuroblast Selection Is Gated by Notch, Snail, SoxB, and EMT Gene Interplay. Cell Reports, 29(11), 3636–3651.e3.

Paese CLB, et al  (2018). A SoxB gene acts as an anterior gap gene and regulates posterior segment addition in a spider. eLIFE, 7:e37567

Niwa H, et al (2016). The evolutionally-conserved function ofgroup B1 Sox family members confers theunique role of Sox2 in mouse ES cells. BMC Evolutionary Biology, 1–12.

Ferrero E., et al (2014). SoxNeuro orchestrates central nervous system specification and differentiation in Drosophila andis only partially redundant with Dichaete. Genome Biology and Evolution, 15(5), R74. doi:10.1186/gb-2014-15-5-r74