Fixed-term

Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Research question The life of mammals starts with fertilization of an egg, which subsequently undergoes multiple rounds of cell division and develops into a complete organism. During mammalian pre-implantation, transcription factors (TFs) play a crucial role in the first lineage segregation into the inner cell mass and trophectoderm (TE), which give rise to the embryo proper and extraembryonic tissue (e.g. placenta), respectively. Among TFs, specialized TFs known as pioneer TFs, play key roles in cell differentiation and reprogramming. Pioneer TFs have unique abilities that bind nucleosomal DNA and modulate epigenetic and chromatin states by facilitating the recruitment of chromatin remodelers and histone modifiers. CDX2 and GATA3 are key pioneer TFs that commit TE cell lineage in mice. However, how these pioneer TFs drive TE gene regulatory networks at the chromatin level during the first lineage segregation remains poorly understood. Our research will establish the fundamental mechanisms underpinning TE lineage commitment, offering a new perspective on gene regulation with far-reaching implications for chromatin biology. Kobayashi lab uses a multidisciplinary approach to address this question using state-of-the-art methods, including low-input genomics, proteomics, biochemistry, and structural biology. We seek to unravel fundamental principles of gene regulation and epigenetic reprogramming in mammalian development and gain insights into defects in the process that affect fertility. The project This PhD project aims to uncover the molecular basis by which pioneer TFs CDX2 and GATA3 engage with nucleosomes and associated co-factors to function as transcriptional activators and repressors. The student will purify recombinant proteins and reconstitute defined complexes with nucleosomes in vitro. Using biochemical and biophysical approaches, the student will investigate how pioneer TFs engage with nucleosomes together with specific co-factors and how these interactions alter chromatin structure. The reconstituted complexes will be further visualized using cryo-electron microscopy (cryo-EM) to determine their molecular basis. If successful, the project also provide training in embryology to investigate how specific amino acid(s) impact on developmental outcomes and gene regulation in vivo. What you will gain Expertise in recombinant protein purification and in vitro nucleosome reconstitution Experience in designing and analysis for biochemical and biophysical experiments Training in structural biology using cryo-EM Skills for single-particle analysis using software such as RELION and CryoSPARC Training in mouse embryology techniques Related publications: Kobayashi W, Michael AK, Ruangroengkulrith S, Kümmecke M, Tachibana K. Protocol for integrative analysis of transcription factor-nucleosome interactions using SeEN-seq and cryo-EM structure determination. STAR Protoc. 2025, 7:104295. Kobayashi W, Sappler H. A, Bollschweiler D, Kümmecke M, Basquin J, Arslantas E, Ruangroengkulrith S, Hornberger R, Duderstadt K, Tachibana K. Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by minor groove anchor competition. Nat Struct Mol Biol. 2024, 31:757-766. Gassler J*, Kobayashi W*, Gáspár I*, Ruangroengkulrith S*, Mohanan A, Gómez Hernández L, Kravchenko P, Kümmecke M, Lalic A, Rifel N, Ashburn RJ, Zaczek M, Vallot A, Cuenca Rico L, Ladstätter S, Tachibana K. Zygotic genome activation by the totipotency pioneer factor Nr5a2. Science. 2022, 378:1305-1315. Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Dr Wataru Kobayashi Principal Investigator, Principal Investigator wkobayashi001@dundee.ac.uk Second supervisor Person Professor Tom Owen-Hughes Professor t.a.owenhughes@dundee.ac.uk +44 (0)1382 385796

Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. The cells in your retina that fire as you read this text, the neurones in your brain that help you make sense of its content, the muscle cells that make your heart beat: They all contain the same genetic code, the identical DNA molecules, passed down during countless cell divisions from a single zygote. And yet, all these cells come in strikingly different shapes and with highly specialised functions. These phenotypical differences are manifestations of the activation and silencing of distinct genetic programs. Regulation of these programs happens through the tightly orchestrated binding and dissolution of myriad transcription factors. These binding events are facilitated – or prevented – by epi-genetic changes to the chromatin landscape. Epigenetic mechanisms are, for instance, chemical changes to the DNA molecule that do not change the DNA sequence itself but affect its local accessibility. These epigenetic mechanisms thus allow for the required plasticity during differentiation but also contribute towards maintaining cellular identity. Malfunction of the epigenetic machinery is, therefore, highly associated with many pathologies, including developmental disorders and tumorigenesis. Epigenetic events leave lasting footprints on the genome, which can be measured using high-throughput sequencing tools. As epigenomic patterns differ between cell types, integrate external signals and dynamically change during ageing, understanding their significance for transcription regulation remains challenging. This project will investigate and develop new Machine Learning approaches to analyse and interpret state-of-the-art interventional single-cell time-course experiments on engineered ES cell lines, interrogating the epigenetic machinery and its action on gene regulation and expression. The student will join the Computational Epigenomics Group in the School of Life Sciences and will closely collaborate with experimentalists in the division for Molecular Cell and Developmental Biology. An appetite to learn across disciplines is strongly required for this project. Upon completing their PhD, the student will have gained new skills encompassing state-of-the-art machine learning methods, epigenetics, chromatin biology, gene regulation, and sequencing data analysis. The student will benefit from interactions with a diverse and multidisciplinary scientific community, and will use state-of-the-art facilities. Further reading: Blümli et al (2021). Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription. https://www.sciencedirect.com/science/article/pii/S2211124721014169?via%3Dihub Hawkins-Hooker et al (2023) Getting personal with epigenetics: towards individual-specific epigenomic imputation with machine learning. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406842/ Schweikert et al. (2013). MMDiff: quantitative testing for shape changes in ChIP-Seq data sets.  https://link.springer.com/article/10.1186/1471-2164-14-826 Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Dr Gabriele Schweikert Principal Investigator/Senior Lecturer g.schweikert@dundee.ac.uk +44 (0)1382 388895 Second supervisor Person Professor Tom Owen-Hughes Professor t.a.owenhughes@dundee.ac.uk +44 (0)1382 385796

Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Human cells store their genetic information in 46 chromosomes. To maintain this vital genetic information, a complete set of chromosomes must be inherited precisely by each daughter cell after cell division. Errors in this process cause cell death and various human diseases, such as spontaneous miscarriage during pregnancy, genetic abnormalities and cancers. Our research goal is to understand the fundamental mechanisms that ensure accurate chromosome inheritance when cells divide. These mechanisms involve how chromosomes efficiently and correctly interact with a cellular apparatus called the mitotic spindle that subsequently moves chromosomes into the new daughter cells. The Tanaka group has been studying molecular mechanisms for chromosome interaction with the mitotic spindle, using budding yeast and human cells. While budding yeast represents a simple model system to study evolutionarily conserved mechanisms, human cells provide information directly relevant to human diseases. The Tanaka group’s pioneering works in budding yeast revealed how chromosomes efficiently interact with the mitotic spindle and how errors in this process are subsequently corrected [1]. Moreover, in human cells, his group recently discovered a novel mechanism that defines chromosome positioning to facilitate interaction with the mitotic spindle [2]. Crucially, many cancer cells lack this chromosome positioning mechanism. This discovery gives new insight into how cancer cells develop chromosome instability, which causes chemotherapy resistance and results in poor prognosis. Meanwhile, G. Barton is the academic lead of the Data Analysis Group (DAG), who has been developing computer simulation of chromosome interaction with the mitotic spindle, in collaboration with the Tanaka group [3]. Such simulation and mathematical modelling help us understand how multiple mechanisms cooperate and minimise errors in this process to prevent chromosome instability, a hallmark of cancer cells. This PhD project will further explore mechanisms for chromosome interaction with the mitotic spindle, using advanced live-cell imaging and mathematical modelling. For example, the project will address how chromosome positioning and interaction with the mitotic spindle are coordinated and how the aberrant chromosome interaction with the mitotic spindle is actually removed and replaced with correct interaction. The results from live-cell imaging will be fed into computer simulation to evaluate the complex dynamics on the whole set of chromosomes and to reveal cooperation between multiple mechanisms. The aim of the project is not only to understand mechanisms in normal cells, but also to reveal how the mechanisms go wrong, leading to chromosome instability in cancer cells. The PhD student, who takes this project, will learn methods in molecular genetics, genome editing, advanced live-cell imaging, super-resolution microscopy and image analyses, and will collaborate with bioinformaticians in DAG to develop mathematical modelling and computer simulation. This PhD project will provide a unique opportunity of working on cutting edge biosciences integrating wet-lab and in-silico approaches. References [1] Kalantzaki M et al. Kinetochore–microtubule error correction is driven by differentially regulated interaction modes. Nat Cell Biol, 17, 421-33, (2015). [2] Booth AJR et al. Contractile actomyosin network on nuclear envelope remnants positions chromosomes for mitosis. eLife 8, e46902 (2019). [3] Vasileva V et al. Molecular mechanisms facilitating the initial kinetochore encounter with spindle microtubules. J. Cell Biol, 216, 1609-22 (2017). Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Professor Tomoyuki Tanaka Professor t.tanaka@dundee.ac.uk +44 (0)1382 385814 Second supervisor Person Professor Geoffrey Barton Professor g.j.barton@dundee.ac.uk +44 (0)1382 385860

Funding – self-funded/externally sponsored applicants  (PhD Fees can be found here) Applications are accepted year round Standard Entry dates – January and September Applicants are expected to have a degree (equivalent of Honours or Masters) in a relevant discipline. Drug resistance is a global problem affecting both public and animal health. In recent years, data on drug efficacy and resistance has increasingly become publicly available. However, an understanding of how structural and biological features (e.g. mutations, gene regulation) are related to the emergence of resistance is still in its infancy. We have recently successfully built machine-learning models predicting drug activity in the Gram-negative bacteria E. coli and P. aeruginosa and linking structural with microbiological features such as efflux pump variants. In this project, you will construct models of antimicrobial resistance for animal and human pathogens. You will use molecular modelling and biomolecular simulations to develop a mechanistic understanding of the underlying structure-function relationships and to rationalise the resistance pathways. This work will contribute to the design of improved anti-infectives and to the development of strategies to evade resistance. Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.  We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education. How to apply Please contact the principal project supervisor to discuss your interest further, see supervisor details below. For general enquiries, contact SLS-PhDAdmin@dundee.ac.uk Supervisors Principal supervisor Person Professor Ulrich Zachariae Professor u.zachariae@dundee.ac.uk +44 (0)1382 381261 Second supervisor Person Professor Rastko Sknepnek Professor r.sknepnek@dundee.ac.uk +44 (0)1382 385699