A5084034730- Epigenetics and DNA Methylation
- Asthma and respiratory diseases
- Genomics and Chromatin Dynamics
- Immune Response and Inflammation
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- T-cell and B-cell Immunology
- TGF-β signaling in diseases
- Estrogen and related hormone effects
- Adrenal Hormones and Disorders
- Respiratory viral infections research
- Neonatal Respiratory Health Research
- Cancer-related molecular mechanisms research
- RNA Research and Splicing
- IL-33, ST2, and ILC Pathways
- Nuclear Structure and Function
- Cytokine Signaling Pathways and Interactions
- Ubiquitin and proteasome pathways
- Acute Myeloid Leukemia Research
- Receptor Mechanisms and Signaling
- Circular RNAs in diseases
- RNA and protein synthesis mechanisms
- Occupational and environmental lung diseases
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Hematopoietic Stem Cell Transplantation
The University of Melbourne
2015-2024
Walter and Eliza Hall Institute of Medical Research
2018-2024
H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes differentiation development. Here, we investigate molecular consequences loss cells deficient both SUV39H1 SUV39H2 (Suv39DKO), major mammalian histone methyltransferase enzymes that catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression Suv39DKO cells, with these differentially expressed...
The long noncoding RNA (lncRNA) GAS5 has been found to act as a decoy for the glucocorticoid receptor (GR), thus implicating potential regulator of sensitivity and resistance. Airway smooth muscle (ASM) cells airway epithelial (AEC) play an important role in pathogenesis persistence asthma other chronic airways diseases. These structural cell types are also cellular targets anti-inflammatory actions glucocorticoids. In this study, we sought examine relevance resistance ASM AEC. We provide...
BACKGROUND AND PURPOSE The lung adenocarcinoma cell line, A549, undergoes epithelial‐mesenchymal transition (EMT) in response to TGF‐β. Glucocorticoids do not prevent the EMT response, but TGF‐β induced resistance cytokine‐regulatory action of glucocorticoids. We sought characterize impairment glucocorticoid A549 cells. EXPERIMENTAL APPROACH cells were exposed for up 96 h before treatment and challenge with IL‐1α assess regulation IL‐6 CXCL8 production. Nuclear localization receptor α (GRα)...
During cellular differentiation chromosome conformation is intricately remodelled to support the lineage-specific transcriptional programs required for initiating and maintaining lineage identity. When these changes occur in relation cell cycle, division time response activation signals has yet be explored, although it been proposed during DNA synthesis or after mitosis. Here, we elucidate conformational B lymphocytes as they differentiate expand from a naive, quiescent state into antibody...
Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition TGF-β limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover little-known connection between signalling casein kinase (CK) activity. have examined the abundance CK1 delta epsilon (CK1δ/ε) in lung tissue from IPF patients non-diseased controls, investigated whether...
2-Methoxyestradiol (2MEO) is an endogenous metabolite of 17β-estradiol that interacts with estrogen receptors and microtubules. It has acute anti-inflammatory activity in animal models not attributable to known antiproliferative or antiangiogenic actions. Because macrophages are central the innate inflammatory response, we examined whether suppression macrophage activation by 2MEO could account for some its effects. Inflammatory mediator production stimulated lipopolysaccharide (LPS)...
We have previously shown that transforming growth factor-beta (TGF-beta) impairs glucocorticoid (GC) function in pulmonary epithelial cell-lines. However, the signalling cascade leading to this impairment is unknown. In present study, we provide first evidence TGF-beta GC action differentiated primary air-liquid interface (ALI) human bronchial cells (HBECs). Using BEAS-2B cell line, also a systematic examination of known pathways activated by TGF-beta, order ascertain molecular mechanism...
Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) influenza A (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a factor we have previously shown impair GC action in human epithelial cells through activation activin-like kinase 5 (ALK5), type 1 receptor...
Abstract Glucocorticoids are commonly used to prevent chemotherapy-induced nausea and vomiting despite a lack of understanding their direct effect on cancer progression. Recent studies suggest that glucocorticoids inhibit cell migration. However, this action has not been investigated in estrogen receptor (ER)-negative breast tumour cells, although activation the glucocorticoid (GR) is associated with worse prognosis ER-negative cancers. In study we have explored migration MDA-MB-231 human...
Abstract Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency an inflammatory niche exacerbate tissue pathology. Using both genetic pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils sites in mice. We demonstrate a selective inhibitor (A-1331852) has therapeutic potential by causing apoptosis human ex vivo. Moreover, murine models acute chronic disease,...
Abstract Stably silenced genes that display a high level of CpG dinucleotide methylation are refractory to the current generation dCas9-based activation systems. To counter this, we create an improved system by coupling catalytic domain DNA demethylating enzyme TET1 with transcriptional activators (TETact). We show TETact demethylation-coupled is able induce transcription suppressed genes, both individually and simultaneously in cells, has utility across number cell types. Furthermore, can...
Strategies that intervene with the development of immune-mediated diseases are urgently needed, as current treatments mostly focus on alleviating symptoms rather than reversing disease. Targeting enzymes involved in epigenetic modifications to chromatin represents an alternative strategy has potential perturb function lymphocytes drive immune response. Here, we report 2 major silencing pathways increased after T cell activation. By specific inactivation these molecules compartment vivo,...
Abstract Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of frequently phosphorylated damage, promotes cancer progression, but its role remains unclear. Here, we report molecular characterisation full-length, demonstrating preference for binding open functioning as sliding clamp. We identified phosphate interacting motif within CTD that dictates ATP hydrolysis...
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Cortisol, a physiologic glucocorticoid (GC), is essential for growth and differentiation of the airway epithelium. Epithelial function influences inflammation in chronic respiratory diseases. Synthetic GCs, including inhaled corticosteroids, exert anti-inflammatory effects epithelium by transactivation genes inhibition proinflammatory cytokine release. We examined effect cortisol on actions synthetic GCs epithelium, demonstrating that acts like partial agonist at GC receptor (GR), limiting...
The proximity pattern and radial distribution of chromosome territories within spherical nuclei are random non-random, respectively. Whether this is conserved in the partitioned or lobed polymorphonuclear cells unclear. Here we use paint technology to examine all 46 chromosomes hundreds single human neutrophils - an abundant famously immune cell. By comparing randomly shuffled controls validating with orthogonal conformation capture technology, show for first time that distribute neutrophil...