The focus of my research is understanding the role of chromatin and nuclear organisation in controlling gene expression during the development of the immune system.​
​B lymphocytes are cells of the immune system that produce antibodies (immunoglobulins), which recognise and inactivate foreign antigens like bacteria. To cope with the enormous numbers of foreign antigens encountered during our lifespan, these cells must produce millions of different antibodies.
Recombination or ‘shuffling' of genes in the immunoglobulin heavy chain (IgH) locus is the first step in generating this huge repertoire.
Special ‘marks’ on the chromatin are thought to underlie the complex choice of gene segments in the multigenic immunoglobulin gene families, that can be recombined during B cell development to produce a large diversity of functional antibody molecules.
My research investigates non-coding RNA transcription (ie generation of transcripts that do not produce protein) in specific parts of the immunoglobulin cluster, which may play a directive role in V(D)J recombination, or mark epigenetic control regions.
Only one of each gene type is used in an individual cell and the resulting DNA sequence encodes a unique IgH, which is expressed with an Ig light chain as a unique highly specific antibody in each cell.
Temporal control is central to deploy and coordinate genetic programs during development. At present, there is limited understanding of the molecular mechanisms that govern the duration and speed of developmental processes. Timing mechanisms may run in parallel and/or interact with each other to integrate temporal signals throughout the organism. In this piece, we consider findings on the extrinsic control of developmental tempo and discuss the intrinsic roles of cell cycle, metabolic rates, protein turnover, and post-transcriptional mechanisms in the regulation of tempo during neural development.
Regulation of transcription is central to the emergence of new cell types during development, and it often involves activation of genes via proximal and distal regulatory regions. The activity of regulatory elements is determined by transcription factors (TFs) and epigenetic marks, but despite extensive mapping of such patterns, the extraction of regulatory principles remains challenging.
Obesity is associated with increased ovarian inflammation and the establishment of leptin resistance. We presently investigated the role of impaired leptin signalling on transcriptional regulation in granulosa cells (GCs) collected from genetically obese mice. Furthermore, we characterised the association between ovarian leptin signalling, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and macrophage infiltration in obese mice. After phenotype characterisation, ovaries were collected from distinct group of animals for protein and mRNA expression analysis: (i) mice subjected to a diet-induced obesity (DIO) protocol, where one group was fed a high-fat diet (HFD) and another a standard chow diet (CD) for durations of 4 or 16Â weeks; (ii) mice genetically deficient in the long isoform of the leptin receptor (ObRb; db/db); (iii) mice genetically deficient in leptin (ob/ob); and (iv) mice rendered pharmacologically hyperleptinemic (LEPT). Next, GCs from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Transcriptional analysis revealed opposing profiles in genes associated with steroidogenesis and prostaglandin action between the genetic models, despite the similarities in body weight. Furthermore, we observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice or in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob and 16-wk HFD-fed mice. We concluded that leptin signalling regulates NLRP3 inflammasome activation and the expression of M1 markers in the ovaries of obese mice in an ObRb-dependent and ObRb-independent manner. Furthermore, we found no changes in the expression of leptin signalling and NLRP3 inflammasome genes in GCs from db/db and ob/ob mice, which was associated with no effects on macrophage infiltration genes, despite the dysregulation of genes associated with steroidogenesis in homozygous obese db/db. Our results suggest that: (i) the crosstalk between leptin signalling, NLRP3 inflammasome and macrophage infiltration takes place in ovarian components other than the GC compartment; and (ii) transcriptional changes in GCs from homozygous obese ob/ob mice suggest structural rearrangement and organisation, whereas in db/db mice the impairment in steroidogenesis and secretory activity.