Dr Danuta Mariola Jeziorska
Senior Postdoctoral Research Scientist
Decoding how genes are regulated
I am a senior Postdoctoral Research Scientist, working under the guidance of Prof Doug Higgs in 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 myoblasts (C2C12). 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.
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.
DNA METHYLATION OF TRANSCRIBED CPG ISLANDS DEPENDS ON THEIR TRANSCRIPTIONAL ACTIVITY DURING DIFFERENTIATION AND 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 analyzing specific loci and using genome-wide 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 CGI methylation in normal development and differentiation, and in human disease.
VISUALISING ALPHA GLOBIN TRANSCRIPTION IN LIVING CELLS IN REAL TIME
Live cell analysis has shown that transcription is a dynamic process consisting of a series of bursts of activity, interrupted by an off stage when no transcript is produced. This so called transcriptional bursting is conserved from bacteria to mammals; despite its prevalence however, it is poorly understood. I have generated an experimental model to visualize transcription of the well-characterised alpha-globin gene. This system enables us to study the real-time dynamics of transcription in individual living cells, in order to further our understanding of how genes are switched on and off during erythroid differentiation. This system will be further used to answer fundamental questions in the field of transcription regulation, including the role of enhancers in modulating the dynamics of transcription.
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