Shi Group Research Overview
Research background - fundamental epigenetic discoveries
A major source of epigenetic information in a cell is stored in the form of chemical modifications within its DNA, RNA and histone proteins. Many of these modifications are dynamically created (written), recognised (read), and removed (erased) throughout the life cycle of eukaryotic organisms. Over the last few decades, a central focus of our research has been to understand the fundamental mechanisms that regulate chromatin, which impact biological processes. With the discovery of the first histone methyl eraser, LSD1, in 2004, our group demonstrated that histone methylation is dynamically regulated, which overturned the long-held dogma that such modifications were static and irreversible. Building on this and our other fundamental epigenetic research, including RNA modification, we are now applying these discoveries to improve our understanding of cancer.
Epigenetics and cancer
Acute Myeloid Leukaemia
Acute myeloid leukaemia (AML) is a deadly cancer in need of more effective treatments. A general property of AMLs is defective differentiation, where the self-renewing leukaemic stem cell undergoes limited differentiation to generate the leukaemic blast, an immature form of white blood cell that is incapable of further development into the mature myeloid effector cells. Studies from our lab and others found that inhibition of the lysine demethylase LSD1 partially overcomes the differentiation barrier in AMLs and promotes committed maturation and programmed cell death of leukaemic cells. We aim to identify and validate the mechanisms and clinical relevance of drug strategies that combinatorially target chromatin modifications and other pathways, including metabolic pathways, to induce therapeutic differentiation of AML.
Paediatric Brain Cancer
Diffuse Intrinsic Pontine Glioma (DIPG) is a highly aggressive and difficult to treat tumour located in a region of the brainstem that controls the body’s critical functions such as heart rate, breathing and blood pressure. Sequencing of these cancers has identified mutations in genes encoding the histone proteins. The H3K27M mutation, observed in ~80% DIPGs, is localised to the histone H3 tail region that is subject to extensive covalent modification, suggesting that this mutation might disrupt chromatin organisation and function. We successfully performed the first CRISPR-Cas9 screens for regulators of H3K27M DIPG viability/proliferation using a chromatin-focused sgRNA library. We are now performing mechanistic studies to follow-up on hits from these screens to determine if and how various chromatin regulators contribute to changes in glioma chromatin structure, histone modification, gene expression and differentiation. Ultimately, insights gained from these studies aimed at revealing epigenetic vulnerabilities in H3K27M mutant tumours may inform the development of more effective treatment strategies for this type of brain cancer.
Enabling immune checkpoint blockade therapy by manipulating epigenetic regulators
Cancer immunotherapy, particularly PD-(L)1-directed immune checkpoint blockade (ICB) therapy, has revolutionised cancer treatment. However, two major issues remain to be resolved. One issue is that a large percentage of cancer patients do not respond to ICB therapy, and these tumours are considered poorly immunogenic or “cold” tumours. The other issue is that even immunogenic tumours may lack sustainable responses to ICB due to multiple reasons including T cell exhaustion. Thus, there is a clear unmet clinical need to extend the benefits to non-responders and to achieve a long-lasting therapeutic effect. Our recent study using LSD1 as an example suggests that epigenetic regulators play critical roles in modulating antitumor immunity and tumour responses to immunotherapy. We are interested in uncovering a network of epigenetic regulators and mechanisms of action that impact tumour response to host immunity and immunotherapy, and epigenetic mechanisms that control T cell reinvigoration.