Our group investigate how DNA changes as we age
The aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. Our research aims at understanding how DNA packaging and structure change as we age and whether we can target ageing related structural features to prevent ageing related disorders such as Dementia and Cancer.
In the ChemBioAging lab we exploit a range of chemical biology tools to investigate the fundamental role of DNA secondary structures and epigenetic modification in ageing biology. Our mission is to identify novel targets to exploit for therapeutic intervention of rare accelerating ageing syndromes and promote healthy ageing across the life course.
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Guanine rich DNA sequences are known to fold into a globular structural arrangement also known as G-quadruplex (G4) DNA. Over the past few years, it has been demonstrated that G4s can be detected in human cells by means of IF and ChIP-Seq experiments, suggesting a potential biological role of this structures for cellular homeostasis. Accumulation of unresolved G4 structures leads to genomic instability, a hallmark of ageing and cancer.
Our group uses a range of chemical-biology tools to monitor how G4s prevalence and dynamics change as we age, to underpin genetic and epigenetic factors that might promote formation of G4 structures during ageing. Our ultimate goal is to develop small molecule ligands to target and unfold G4 structures at specific genomic loci to prevent genomic instability and ageing related disorders like cancer.
Specific research goals include:
- Development of G4-disrupting small molecules
- Understanding the molecular mechanism of G4 unfolding by helicases
- Underpinning epigenetic changes that are associated with ageing and can promote G4 formation
Single Molecule Tracking
DNA is one of the most targeted biomolecules as it is involved in the regulation of many biological processes, including cell-growth and gene-expression. Although targeting of the canonical double helical form of DNA has been extensively investigated in the past, increasing interest is growing around the targeting of non-canonical DNA structures. Among these, DNA G-quadruplex (G4) structures are of particular interest as recent evidence suggests that they could be involved in regulating gene expression. Despite the increasing number of scientific observations demonstrating the relevance of G4s in various biological processes, there is still a significant amount of skepticism about the actual relevance and existence of these structures in living cells.
Our group uses single molecule tracking (SMT) microscopy to investigate the dynamic of DNA structures formation in real time in living cells with respect to cell-type and biological responses. SMT enables visualisation of individual labelled probes (e.g. small molecules or proteins) and allow investigation of their cellular dynamics in real time. We employ SMT platforms to unravel cause-effect of G4 formation in relation to fundamental biological processes like transcription and telomere maintenance. Similarly, we employ SMT to investigate how Transcription Factors (TF) binding can be affected by chromatin changes associated with ageing.
The tools and the SMT platform established in our group are expected not only to improve the toolkit available to monitor dynamically biological mechanisms in real-time, but also to shed light on the molecular mechanisms of biologically relevant processes that will be beneficial for the broadest scientific community.
DNA Methyl Transferases
Several diseases result from aberrant gene expression and dysfunction; cancer is one of the most studied examples. Epigenetic marks, such as DNA methylation, induce chromatin-remodeling events that alter gene expression. Cancers with acquired resistance to chemotherapy are often epigenetically reprogrammed, adapting to resist in the presence of the therapeutic agents. Similarly, during ageing chromatin architecture is altered by uncontrolled methylation, which induces transcriptional disfunctions and triggers ageing related conditions. Although several molecules have been designed to inhibit DNA-methyltransferases (DNMTs), a general lack of gene-specificity shared among these drugs strongly limits their application for both clinical applications and basic research.
We aim at overcoming these limitations by exploring a novel DNMTs inhibition strategy that relies on targeting the DNA substrate rather than the enzyme itself, enabling site-specific inhibition of the enzyme. The development of these ligands will set a new approach for restoring expression of important tumor suppressor genes and on the generation of novel therapeutic agents, providing new insights on the impact of DNA-methylation in cancer biology and its contribution to drug-resistance mechanism.
Specific research goals include:
- Synthesis of novel molecules capable of selectively disrupting DNMT-DNA interactions
- PNAs coupling of the identified inhibitors to achieve sequence selectivity
- Investigation of MHL1 and RASSF1A as targets for ovarian and breast cancer treatment