Epigenetics in Human Health and Disease Laboratory

Melbourne, Australia

Epigenetics in Human Health and Disease Laboratory

Melbourne, Australia
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Royce S.G.,Murdoch Childrens Research Institute | Royce S.G.,University of Melbourne | Dang W.,Murdoch Childrens Research Institute | Dang W.,Epigenomic Medicine Laboratory | And 12 more authors.
Epigenetics | Year: 2011

Airway remodeling and airway hyperresponsiveness are major aspects of asthma pathology that are not targetedoptimally by existing anti-inflammatory drugs, Histone deacetylase inhibitors have a wide range of effects that maypotentially abrogate aspects of remodeling, One such histone deacetylase inhibitor is valproic acid (2-propylvaleric acid).Valproic acid is used clinically as an anti-epileptic drug and is a potent inhibitor of class I histone deacetylases but alsoinhibits class II histone deacetylases, We used valproic acid as a molecular model of histone deacetylase inhibition invivo in chronic allergic airways disease mice with airway remodeling and airway hyperresponsiveness, Wild-type Balb/cmice with allergic airways disease were treated with valproic acid or vehicle control, Airway inflammation was assessedby bronchoalveolar lavage fluid cell counts and examination of lung tissue sections, Remodeling was assessed bymorphometric analysis of histochemically stained slides and lung function was assessed by invasive plethysmographymeasurement of airway resistance, Valproic acid treatment did not affect inflammation parameters, however, valproicacid treatment resulted in reduced epithelial thickness as compared with vehicle treated mice (p < 0.01), reducedsubepithelial collagen deposition (p < 0.05) and attenuated airway hyperresponsiveness (p < 0.05 and p < 0.01 for thetwo highest doses of methacholine, respectively), These findings show that treatment with valproic acid can reducestructural airway remodeling changes and hyperresponsiveness, providing further evidence for the potential use ofhistone deacetylase inhibitors for the treatment of asthma. © 2011 Landes Bioscience.

Keating S.,Epigenetics in Human Health and Disease Laboratory | El-Osta A.,Epigenetics in Human Health and Disease Laboratory | El-Osta A.,Baker IDI Heart and Diabetes Institute | El-Osta A.,University of Melbourne | El-Osta A.,Monash University
Clinical Genetics | Year: 2013

Diabetes is a multifactorial disease with numerous pathways influencing its progression and recent observations suggest that the complexity of the disease cannot be entirely accounted for by genetic predisposition. A compelling argument for an epigenetic component is rapidly emerging. Epigenetic processes at the chromatin template significantly sensitize transcriptional and phenotypic outcomes to environmental signaling information including metabolic state, nutritional requirements and history. Epigenetic mechanisms impact gene expression that could predispose individuals to the diabetic phenotype during intrauterine and early postnatal development, as well as throughout adult life. Furthermore, epigenetic changes could account for the accelerated rates of chronic and persistent microvascular and macrovascular complications associated with diabetes. Epidemiological and experimental animal studies identified poor glycemic control as a major contributor to the development of diabetic complications and highlight the requirement for early intervention. Early exposure to hyperglycemia can drive the development of complications that manifest late in the progression of the disease and persist despite improved glycemic control, indicating a memory of the metabolic insult. Understanding the molecular events that underlie these transcriptional changes will significantly contribute to novel therapeutic interventions to prevent, reverse or retard the deleterious effects of the diabetic milieu. © 2013 John Wiley & Sons A/S.

Maxwell S.S.,Epigenetics in Human Health and Disease Laboratory | Pelka G.J.,Embryology Unit | Tam P.P.,Embryology Unit | El-Osta A.,Epigenetics in Human Health and Disease Laboratory
RNA biology | Year: 2013

The discovery that Rett syndrome (RTT) is caused by mutation of the methyl-CpG-binding-protein MeCP2 provided a major breakthrough in understanding the neurodevelopmental disorder and accelerated MeCP2 research. However, gene regulation by MeCP2 is complicated. The current consensus for MeCP2 remains as a classical repressor complex, with major emphasis on its role in methylation-dependent binding and repression. However, recent evidence indicates additional regulatory roles, suggesting non-classical mechanisms in gene activation. This has opened the field of MeCP2 research and suggests that the gene targets may not be the usual suspects, that is, dependent only on DNA methylation. Here we examine how chromatin binding and sequence preference may confer MeCP2 functionality, and connect relevant pathways in an active genome. Finding both genomic and proteomic evidence to indicate MeCP2 spliceosome interaction, we consequently discovered broad MeCP2 enrichment of the transcriptome while our focus toward long non-coding RNA (lncRNA) revealed MeCP2 association with RNCR3. Our data may indicate an as-yet-unappreciated role between lncRNA and MeCP2. We hypothesize that ncRNA may mediate chromatin-remodeling events by interacting with MeCP2, thereby conferring changes in gene expression. We consider that these results may suggest new mechanisms of gene regulation conferred by MeCP2 and its interactions upon chromatin structure and gene function.

Keating S.T.,Epigenetics in Human Health and Disease Laboratory | El-Osta A.,Epigenetics in Human Health and Disease Laboratory
Epigenetics : official journal of the DNA Methylation Society | Year: 2013

Posttranslational histone modifications define chromatin structure and function. In recent years, a number of studies have characterized many of the enzymatic activities and diverse regulatory components required for monomethylation of histone H3 lysine 4 (H3K4me1) and the expression of specific genes. The challenge now is to understand how this specific chemical modification is written and the Set7 methyltransferase has emerged as a key regulatory enzyme mediating methylation of lysine residues of histone and non-histone proteins. In this review, we comprehensively explore the regulatory proteins modified by Set7 and highlight mechanisms of specific co-recruitment of the enzyme to activating promoters. With a focus on signaling and transcriptional control in disease we discuss recent experimental data emphasizing specific components of diverse regulatory complexes that mediate chromatin modification and reinterpretation of Set7-mediated gene expression.

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