Danuta Mariola Jeziorska
Honorary Senior Scientist
Decoding how genes are regulated
I am a Honorary Senior Scientist with interest in decoding how genes are regulated.
Prior to that I was a senior Postdoctoral Research Scientist, working under the guidance of Prof Doug Higgs in Gene Regulation lab, at the MRC Molecular Haematology Unit at the MRC Weatherall Institute of Molecular Medicine, University of Oxford. My research focuses on decoding how genes are regulated. Before moving to Oxford, I completed PhD in Systems Biology from the University of Warwick and obtained a BSc degree in Biotechnology from the University of Silesia in Poland.
I have dedicated the last 12 years of my scientific career to study how mammalian genes are regulated and how their deregulation is linked with human disease.
I focused my PhD to study the role of the non-coding DNA in regulation of gene expression. I integrated computational and experimental approaches to decipher the regulation of the Hes1 gene in myoblast cell line. Using comparative genomics, I identified regulatory elements, called switches, that interact with the Hes1 promoter in the 3D genome; and defined the transcription factor binding sites and trans-acting factors responsible for their function, contributing to further understanding of the Hes1 regulatory mechanism and implicating the Hippo signalling pathway in control of Hes1 expression. Finally, I investigated the dynamics of the 3D genome architecture of Hes1 across time at different stages of its oscillatory expression, providing insights into the 4D Nucleome.
Additionally, I generated destabilised multimerised fluorescent reporters (with half-life of 30 and 90 mins) for real-time live cell imaging of gene expression at the single cell level, which are currently used by several collaborators.
In my current role, I am studying how genes are turn on and off during red blood cell formation, with particular focus on the role of epigenetics and dynamics of transcription. More details below:
I have established an experimental model system that allows us to visualise the alpha globin gene transcription dynamics in individual living cells in real time. This model is a powerful tool to study the fundamental principle of how genes are turn on and off during differentiation and development. At present we are investigating the transcription kinetics of the alpha globin gene at different stages of erythropoiesis and the role of enhancers (switches) in modulating this process.
In collaborative work with Prof Veronica Buckle lab and others, we will employ this model to study the enhancer-promoter communication together with transcription dynamics at the single cell level as the alpha globin gene is turn on during erythropoiesis. This will provide us with an optical insight into the dynamic relationship between gene activity and the changes in the 4D nucleome (genome architecture) within individual living cells.
I have received a MSIF award to establish tools for dual RNA labelling in living cells with aim to visualise how shared set of enhancers (switches) regulate expression of two identical genes.
I proposed a general model of how transcription could act as a primary determinant of the patterns of DNA methylation of intragenic CGIs during differentiation, and in human disease.
Methylation of CpG dinucleotides is an essential epigenetic modification that plays a pivotal role in transcription regulation. Most CpG dinucleotides in the genome are methylated, with the exception of those within CpG rich regions called CpG islands (CGIs). While CGIs associated with promoters nearly always remain unmethylated, many of the ∼9,000 CGIs lying within gene bodies become methylated during development and differentiation. Both promoter and intragenic CGIs may also become abnormally methylated: for example, as a result of genome rearrangements or malignancy. The epigenetic mechanisms by which some CGIs become methylated but others, in the same cell, remain unmethylated are poorly understood. By genetically engineering multiple model systems to define the principle of how CGIs are methylated and by conducting genomics analyses, I have shown that transcription running across CGIs, associated with specific chromatin modifications, is required for DNA methyltransferase 3B (DNMT3B)-mediated DNA methylation of many naturally occurring intragenic CGIs. Importantly, we have also shown that a subgroup of intragenic CGIs is not sensitive to this process of transcription-mediated methylation, and that this correlates with their individual intrinsic capacity to initiate transcription in vivo. This has allowed us to propose a general model of how transcription could act as a primary determinant of the patterns of DNA methylation of intragenic CGIs in normal development and differentiation, and in human disease. As well as suggest a mechanism for silencing of alternative promoter CGIs of genes with multiple isoforms.
My talk on How a rare case of alpha thalassemia led to the discovery of new epigenetic silencing mechanism from Cold Spring Harbor Laboratory Conference, New York, 2017.
Outside my academic interests, I am a biotech entrepreneur. I am a CEO and co-founder of Oxford University spinout, Nucleome Therapeutics, that aims to solve the non-coding regulation of the genome to help deliver life changing treatments. We are using the 3D nuclear architecture of the genome and AI powered computational genomics platform to transform drug target discovery and help deliver the next generation of genetically guided therapeutics.
Prior to that, in 2015, I co-founded Innovation Forum Oxford with aim to accelerate innovation and aid research translation. I led the branch for two years and together with IFO team provided entrepreneurial training to hundreds of scientists in the health and life-sciences sector and built a platform for showcasing science and knowledge exchange that continues to bring together hundreds of members of academia, industry, the NHS and policy makers. IFO contribution to the Oxford entrepreneurial ecosystem was recognised by three independent nominations (Business Development Office from Medical Science Division, Oxford University Innovation and MRC WIMM) for the 2018 Vice-chancellor Inaugural Innovation Award. I also helped form TechTonic Women, to support women in the technology sector in Oxfordshire, where I was a Director and Board member for the last three years.
For this work I was recognised as one of the Rising Stars in 50 Movers and Shakers in BioBusiness 2018 for supporting innovation from concept to market.
DNA methylation of intragenic CpG islands depends on their transcriptional activity during differentiation and disease.
Jeziorska DM. et al, (2017), Proc Natl Acad Sci U S A, 114, E7526 - E7535
Novel cis-regulatory modules control expression of the Hairy and Enhancer of Split-1 (HES1) transcription factor in myoblasts.
Jeziorska DM. et al, (2012), J Biol Chem, 287, 5687 - 5697
Extracting fluorescent reporter time courses of cell lineages from high-throughput microscopy at low temporal resolution.
Downey MJ. et al, (2011), PLoS One, 6
A systems biology approach to understanding cis-regulatory module function.
Jeziorska DM. et al, (2009), Semin Cell Dev Biol, 20, 856 - 862