Latest AEpiA news
We thought we’d share some brief highlights of Australian epigenetics publications over the last three months:
From La Trobe University in Melbourne, Prof Whelan and team have published an insightful study that “reveals the complex dynamics and interactions of the transcriptome and epigenome during seed germination”. The study identifies the epigenomic and transcriptomic changes that Arabodpsis Thaliana seeds undergo as they transition from an embryo-like to vegetative seedling during germination. Further, by generating a transcription factor network model for germination, the authors identify known and novel regulatory factors that drive seed germination. The paper reveals extensive remodelling of the seed DNA methylome during this period of transformation. https://doi.org/10.1186/s13059-017-1302-3
In a joint effort by the laboratories of Prof Johnstone from the Peter MacCallum Cancer Centre and Dr Hawkins from The Walter and Eliza Hall Institute of Medical Research in Melbourne, Notch 1 signaling has been targeted as a novel therapeutic for T cell acute lymphoblastic leukemia (T-ALL). Using the notch driven T-ALL mouse model the authors investigate the therapeutic possibility of the histone deacetylase inhibitor (HDACi) panobinostat.
The study revealed that the drug was able to regulate T-ALL cellular proliferation, and that this was correlated with a loss of c-Myc expression in these cells. In vivo, Panobinostat treated mice had significantly increased survival compared to vehicle treated control leukemia mouse models.
A collaborative effort between Umeå University in Sweden, the University of Melbourne and Murdoch Children’s Research Institute in Melbourne published a population-based study on grandmaternal smoking during pregnancy and the risk of asthma in grandchildren. Lodge et. al. interrogated prospectively collected data from the national Swedish registries to reveal that “children aged 1-6 years had an increased asthma risk if their grandmothers had smoked during pregnancy.” The study further confirmed that maternal smoking did not modify this relationship.
In Nature Communications this month the group of Prof Susan Clark from the Garvan Institute of Medical Research in Sydney published on the role of the histone variant H2A.Z in enhancer activation in prostate cancer. Valdés-Mora et. al. reveal that an increased level of H2A.Z acetylation correlates with poor prognosis in prostate cancer samples. Using prostate cancer cell line models the study shows that androgen receptor associated enhancers require the incorporation of acetylated H2A.Z for activation and that H2A.Zac is mis-localized at active enhancers in cancer.
The study further demonstrates that acetylation of H2A.Z nucleosomes is associated with ectopic gene activation and epigenetic remodeling of cancer-specific regulatory elements. Collectively the study demonstrates a novel contribution of H2A.Zac in the activation of newly formed enhancers in prostate cancer.
From CSIRO in North Ryde, Sydney Dr Molloy and colleagues address the question of whether “…epigenetic marks present at birth may predict an individual’s future risk of obesity and type 2 diabetes”. For this van Dijk et. al. studied epigenetic marks from blood of newborn children and assessed whether they were associated with body mass index (BMI) and insulin sensitivity in these children later in childhood.In support of growing evidence on the role of epigenetics in programming of metabolic health, the study identified a number of DNA methylation regions at birth that were associated with obesity or insulin sensitivity measurements in childhood. The study also revealed associations between DNA methylation, maternal smoking and birth weight.
Some highlights of Australian epigenetics publications in June-July 2017:
In this elegant study published in Science, Prof Mark Dawson and his team at the Peter MacCallum Cancer Centre in Melbourne partnered with GlaxoSmithKline to modify the epigenetic-based therapy, BET bromodomain inhibitors, to create functionally conserved compounds that are amenable to click chemistry. The authors describe how adding chemically reactive moieties to amenable click chemistry, while preserving the functional integrity of the small molecule (in this case BET inhibitors), allows these molecules to be used in a similar way to how antibodies are used in cell and molecular biology. The study explored the gene regulatory function of BRD4 (bromodomain containing protein 4) and the transcriptional changes induced by BET inhibitors using click proteomics and click sequencing. This approach allowed fluorochromes and/or affinity tags to react with the functionalized drugs in a cellular context and thereby revealed insight into the cellular and molecular mechanisms of the therapy. Using high-resolution microscopy and flow cytometry in an acute leukemia mouse model the authors went on to demonstrate the power of this framework for the preclinical assessment of a wide range of drugs.
In an Australia-wide collaboration, Prof Arthur Georges and colleagues at the University of Canberra’s Institute for Applied Ecology, the National Research Collections Australia of CSIRO; the Garvan Institute of Medical Research, UNSW Sydney and La Trobe University, explore the fact that “in many vertebrates, sex of offspring is determined by external environmental cues rather than by sex chromosomes.” The authors use the unique Australian central bearded dragon, in which chromosomal sex determination is overridden at high temperatures to produce sex-reversed female offspring, to probe into this mysterious process. They show intron retention in two Jumonji family genes, JARID2 and JMJD3, and propose that the perturbation of JARID2/JMJD3 function may alter the epigenetic landscape to override chromosomal sex-determining cues, triggering sex reversal at extreme temperatures. Their observation further extends to alligators and turtles, indicating a reptile-wide mechanism for this phenomenon. The findings were published in Science Advances.
In June, Current Opinion in Genetics & Development published a review by Dr Ozren Bogdanovic of the Garvan Institute of Medical research in Sydney and ProfRyan Lister of the Harry Perkins Institute of Medical Research in Perth. The review systematically explores the “roles of DNA methylation in the establishment and maintenance of cell identity during development.” The authors bring attention particularly to insights obtained from in vivo studies.
From the Centenary Institute at the University of Sydney, Prof John Rasko and colleagues Darya Vanichkina, Ulf Schmitz and Justin Wong discuss the difficulties facing of the newly evolving field of intron retention. The review provides an overview of the challenges of detecting and quantifying retained introns and in determining their effects on cellular phenotype. The authors then highlight approaches that can be used to address these issues.
Dr Stuart Gallagher, Dr Elena Shklovskaya and Prof Peter Hersey of the The Centenary Institute, University of Sydney and the Melanoma Institute Australia, in Sydney, review recent findings on epigenetic modulation to improve cancer immunotherapy. They focus on “the inhibitors of the CTLA4 and PD1 immune checkpoints and epigenetic modifiers of histone acetylation and methylation and DNA methylation.” The review was published in Current Opinion in Pharmacology.
A/Prof Jason Lee from the Queensland Institute of Medical Research (QIMR) in Brisbane led an extensive study on the role of G9a in regulating gene expression in hypoxia. The findings provide “an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker.” The findings demonstrate the potential use of G9a, an epigenetic regulator that methylates H3K9, as a therapeutic target for solid cancers.
Researchers at the Max Planck Institute of Immunobiology and Epigenetics, in Freiburg, Germany have produced a seminal study on the mechanism and consequence of transgenerational epigenetic inheritance. Dr Ozren Bogdanovic, from the Garvan Institute of Medical Research, contributed to the study, which was published in Science last month. Using drosophila as a model system, the researchers elegantly demonstrated that “maternally inherited H3K27me3, propagated in the early embryo, regulates the activation of enhancers and lineage-specific genes during development. Read more in Garvan news.”
Here are some highlights from the Australian epigenetics landscape over April and May 2017:
In an elegant study led by Prof John Rasko from the Centenary Institute, University of Sydney, methylation has been shown to directly regulate intron retention (IR). The study showed that splice junctions with reduced DNA methylation are a mark of IR, and that this is widespread in normal and cancer cells. Lower methylation was shown to be associated with lower MeCP2 density at splice junctions and the authors conclude by demonstrating that lower MeCP2 levels result in reduced recruitment of splicing factors and a loss of splicing at these junctions. The study gives molecular insight into why specific introns are retained in health and disease, whereas others are not, and epigenetic regulation has been demonstrated to be key. Click here for the full text PDF.
In a study led by Dr Clare Stirzaker and Dr Sue Clark at the Garvan Institute of Medical Research in Sydney, Skvortsova et al carry out a comprehensive assessment of currently available genome wide 5-hydroxymethylcytosine profiling approaches. The study compares whole-genome bisulphite/oxidative bisulphite sequencing, Infinium HumanMethylation450 BeadChip arrays coupled with oxidative bisulphite and antibody-based immunoprecipitation and sequencing of hydroxymethylated DNA (hMeDIP-seq). The authors compare the different methods for their precision, sensitivity and cost effectiveness and conclude on the most effective uses for each. To read further – here is the full text PDF.
In the April edition of Science Magazine, Associate Professor Andrew Barron from the Department of Biological Sciences at Macquarie University in Sydney, together with Dr Gene E. Robinson from the Carl R. Woese Institute in Illinois, USA, expounded on the link between epigenetics and the evolution of instinct. The author’s cite epigenetic influences on behaviour that stabilize long-term changes to neural circuits. They then postulate that “evolutionary changes in epigenetic mechanisms may sculpt a learned behaviour into an instinct by decreasing its dependence on external stimuli in favor of an internally regulated program of neural development”. For a thought provoking read, here’s the PDF.
Ira Deveson with Simon Hardwick, Dr Tim Mercer and Professor John Mattick from the Gravan Institute of Medical Research in Sydney have written a broad review of the key studies, and advancements in technology, relating to the mammalian noncoding transcriptome. The review collates and explicates on studies that “shape our understanding of the dimensions, dynamics and biological relevance” of these epigenetic regulators. For the PDF click here.
From the Health Research Institute at the University of Canberra Professor Sudha Rao with Jenny Dunn assess “the promise of combined epigenetic therapy and immunotherapy.” The review gives background into epigenetic therapy, the mechanisms of immune escape in cancer and how epigenetic immunomodulation primes the immune system for immunotherapy. The paper points out that there is robust data to combine the two therapies to improve outcomes for patients with many different cancer types. The PDF of this review can be found here.