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Genomics and immunology

The Genomics and Immunology Laboratory works in two general research areas. Firstly, we are interested in the molecular mechanisms that control immune cell development. The immune system is comprised a diverse range of cell types. Each has to be replenished continuously in appropriate numbers and with appropriate functional properties. This is to ensure that immunity to potential infections is maintained while inappropriate immune responses are suppressed. Any defect in the balance can result in susceptibility to infection or cancer, or the development of autoimmune disease. Secondly, we are interested in the biogenesis and function of non-coding RNAs. We study how these RNAs are transcribed and processed in order to generate functional molecules. We are also interested in understanding the regulation of the microRNA machinery.

Research Themes

Molecular control of T cell development

In order to generate functional T cells, progenitors (thymocytes) must pass through a series of checkpoints within the thymus. This process is regulated by a myriad of molecular mechanisms that involve everything from signal transduction pathways to cytoskeleton movements to gene rearrangements, and we have studied many of these over the years. We are particularly interested in the mechanisms that regulate the CD4 (helper) versus CD8 (cytotoxic) lineage decision in the thymus. Members of the lab are currently studying the roles of non-coding RNAs, epigenetic regulators and cytoskeleton regulators.

MicroRNA biogenesis

Although the biogenesis of most microRNAs is dependent on the RNase III enzymes Drosha and Dicer, several classes of non-canonical microRNAs that are independent of one of these enzymes have been discovered. By comparing cells that lack either Drosha or Dicer, we have identified a number of microRNAs that are independent of Drosha. Drosha-independent microRNAs were previously discovered in flies and worms. In these organisms, the biogenesis of Drosha-independent microRNAs requires the splicing machinery. In mammals, however, we find little evidence for a role of splicing. Alternate processing mechanism(s) must therefore be present in mammalian cells. We are interested in understanding how these non-canonical microRNAs are expressed in mammalian cells and whether they function like canonical microRNAs.

Messenger RNA cleavage and stem cells

We have found that Drosha, one of the RNase III enzymes necessary for microRNA biogenesis, also functions to regulate the stability of certain protein-coding mRNAs. This occurs via recognition and cleavage of secondary stem-loop structures within target mRNAs. We have found that this activity is largely restricted to stem/progenitor populations and appears to be important for regulating the function of these cells. We are interested in understanding how this mRNA cleavage is regulated and ultimately why this mechanism is important for stem/progenitor but not differentiated cells.

Genomic and transcriptional complexities in the immune system

Mammalian genomes contain approximately 20,000 genes. This is only twice the number of genes found in simple organisms such as worms and flies, and half the number of some plants such as potatoes. How is it then possible to achieve the complexity of humans and other mammals with this few genes? One possibility is the derivation of multiple products from each gene. Different gene products can be achieved during transcription by exon skipping or alternate exon usage. The exclusion or inclusion of different exons from a messenger RNA can result in altered protein coding potential and/or regulatory properties. Thus, the number of potential gene products is far greater than 20,000. Furthermore, the utilisation of different regulatory elements (promoters, enhancer, silencers, etc) facilitates complex temporal and tissue-specific gene regulation. We interested in how such complexities impact the development and function of the immune system.

Honours and PhD Projects

Staff

  • Dr Mark Chong
  • Xin Liu
  • Jarrod Skinner
  • Dr Shayarana Gooneratne
  • Dr Lawrence Mok
  • Karen Gu
  • Sean Oh

Publication Highlights

1. Koay HF, Gherardin NA, Enders A, Loh L, Mackay LK, Russ BE, Nold-Petry C., Nold MF, Bedoui S, Chen Z, Corbett AJ, Eckle SBG, Meehan B, d'Udekem Y, Konstantinov I, Lappas M, Liu L, Goodnow CC, Fairlie DP, Rossjohn J, Chong MMW, Turner SJ, Kedzierska K, Berzins SP, Belz GT, McCluskey J, Uldrich AP, Godfrey DI & Pellicci DG (2016), Thymic precursors to the Mucosal-Associated Invariant T cell lineage, Nat Immunol, 17:1300-11.
2. Johanson TJ, Keown AA, Cmero M, Yeo JHC, Kumar A, Lew AM, Zhan Y & Chong MMW (2015), Drosha controls dendritic cell development by cleavage of messenger RNAs encoding inhibitors of myelopoiesis, Nat Immunol, 16:1134-41.
3. Yeo JHC, Skinner JPJ, Bird MJ, Formosa LE, Zhang JG, Kluck RM, Belz GT & Chong MMW (2015), A role for the mitochondrial protein Mrpl44 in maintaining OXPHOS capacity, PLoS One, 10: e0134326.
4. Kobayashi T, Papaioannou G, Mirzamohammadi F, Kozehmyakina E, Zhang M, Blelloch R & Chong MMW (2015), Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage, Osteoarthritis Cartilage, 23:1214-20.
5. Srivastava M, Duan G, Nadia K, Athanasopoulos V, Yeo JHC, Ose T, Hu D, Brown SHJ, Jergic S, Pratama S, Richards S, Verma A, Jones E, Heissmeyer V, Dixon N, Chong MMW*, Babon J* & Vinuesa CG* (2015), Roquin binds microRNA-146a and Argonaute 2 and regulates microRNA homeostasis, Nat Commun, 6:6253. * Co-senior authors
6. Johanson TM, Cmero M, Wettenhall J, Lew AM, Zhan Y & Chong MMW (2015), A microRNA expression atlas of mouse dendritic cell development, Immunol Cell Biol., 93: 480-5.
7. Skinner JP, Keown AA & Chong MMW (2014), The miR-17~92a cluster of microRNAs is required for the fitness of Foxp3+ regulatory T cells, PLoS One, 9:e88997.
8. Knuckles P, Vogt M, Lugert S, Milo M, Chong MMW, Hautbergue GM, Wilson SA, Littman DR & Taylor V (2012, Drosha regulates neurogenesis by controlling Neurogenin2 expression independent of microRNAs, Nat Neurosci, 15:962-9.
9. Kirigin FF, Lindstedt K, Sellars M, Ciofani M, Low SL, Jones L, Bell F, Pauli F, Bonneau R, Myers RM, Littman DR & Chong MMW (2012), Dynamic microRNA gene transcription and processing during T cell development, J Immunol, 188:3257-67.
10. Kaneko H, Dridi S, Tarallo V, Fowler BJ, Gelfrand BD, Cho WG, Kleinman ME, Ponicsan SL, Hauswirth WW, Chiodo VA, Karikó K, Yoo JW, Lee D, Hadziahmetovic M, Song Y, Misra S, Chaudhuri G, Buaas FW, Braun RE, Hinton DR, Zhang Q, Grossniklaus HE, Provis JM, Madigan MC, Milam AH, Justice NL, Albuquerque RJC, Blandford AD, Bogdanovich S, Hirano Y, Witta J, Fuchs E, Littman DR, Ambati BK, Rudin CM, Chong MMW, Provost P, Kugel J, Goodrich JA, Dunaief JL, Baffi JZ & Ambati J (2011), DICER dysregulation induces cytotoxic Alu RNA accumulation in age-related macular degeneration, Nature, 471:325-30.