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Here are some brief highlights of Australian epigenetics publications from the end of last year (2017):

Regulation of H3K4me3 at Transcriptional Enhancers Characterizes Acquisition of Virus-Specific CD8+ T Cell-Lineage-Specific Function

In this study, Professor Turner and colleagues from Monash University and the Doherty Institute at the University of Melbourne have mapped the dynamic regulation of transcriptional enhancers (TEs) in T cells responding to an acute influenza A infection. By doing so they have identified key epigenetic mechanisms that underpin infection specific T cell differentiation, an essential requirement for pathogen clearance. In their publication in Cell Reports the authors used ChIP-seq to map the histone dynamics of 25,000 putative CD8+ T cell transcriptional enhancers differentially utilized during virus-specific T cell differentiation. The study revealed the acquisition of a non-canonical (H3K4me3+) chromatin signature on a subset of dynamically regulated transcriptional enhancers unique to virus-specific CD8+ T cell differentiation. This identified “the genomic location for T cell lineage-specific transcription factor binding required for virus-specific T cell differentiation” and adds vital pieces to the puzzle of infection specific T cell regulation.

For full text by Russ et al., see – http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31779-5

The DNA Methylation Landscape of CD4þ T cells in Oligoarticular Juvenile Idiopathic Arthritis

From Murdoch Children’s Research Institute and the University of Melbourne, Professor Ellis and colleagues report “a lesser relevance of DNA methylation levels in childhood, compared to adult, rheumatic disease”. In their study, published in the Journal of Autoimmunity, the authors used Illumina HumanMethylation450 arrays to perform a genome-scale analysis of CD4. T cell DNA methylation of oligoarticular juvenile idiopathic arthritis patients and age and sex-matched controls. While adult autoimmune rheumatic diseases, such as rheumatoid arthritis, have been associated with altered DNA methylation, the article reveals that the pediatric autoimmune disease, oligoarticular juvenile idiopathic arthritis, does not show substantially altered methylation in oJIA in CD4. T cells.

For full text by Chavez-Valencia et al., see – https://www.sciencedirect.com/science/article/pii/S0896841117305863

Isogenic Mice Exhibit Sexually-Dimorphic DNA Methylation Patterns Across Multiple Tissues

In this study published in BMC Genomics, A/Professor Suter and colleagues from Sydney’s Victor Chang Cardiac Research Institute aimed to understand the extent to which epigenetic states are influenced by sex; given sexual dimorphism is relevant to so many diseases. For this, the authors used DNA methylation patterns from multiple tissues of isogenic male and female mice. Using this model the authors were able to identify “thousands of sexually dimorphic loci”, which they report to be “largely autonomous to each tissue”. The paper reveals that sex influences methylation patterns in a tissue-specific manner and therefore suggests that at least some of the phenotypes that carry gender bias are derived from gender differences in underlying epigenetic states.

For full text by McCormick et al., see – https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-4350-x

Multiple Innovations in Genetic and Epigenetic Mechanisms Cooperate to Underpin Human Brain Evolution

In their Perspective, Dr Guy Barry and Mainá Bitar explore how the human brain differs from those of other species, with a focus on evolutionary adaptations and functionality. Given only 1% of the human genome is unique compared to a chimpanzee, the authors from Brisbane’s QIMR Berghofer Medical Research Institute have collated a wide range of literature on a range of evolutionary adaptations. The review looks at how “Retooling the Protein Toolbox, Innovations in Regulatory RNA, Alterations to the Basic Genetic Code” and “Epigenetics: Fuelling Brain Plasticity and Adaptive Change” explains how our uniquely evolved human brain has come to be. Interestingly for this epigenetics focused audience, the authors site that an estimated 42% of human-chimpanzee gene expression differences are accounted for by epigenetic differences. The review combines “newly discovered genetic and epigenetic mechanisms with more established concepts” to create a more comprehensive picture of this fascinating field.

For full text by Bitar and Barry see – https://academic.oup.com/mbe/article/35/2/263/4644722?searchresult=1

Life and Death of Activated T Cells: How Are They Different from naïve T Cells?

In a review that discusses the contribution of several cell death pathways to the life and death of activated T cells Zhan et al., highlight a mechanism of epigenetic regulation of cell survival unique to activated T cells. The review by Professor Lew and colleagues from the Walter and Eliza Hall Institute of Medical Research and University of Melbourne the collates the efforts made by studies aimed at understanding the survival and death of activated T cells.

For full text by Zhan et al., see – https://www.frontiersin.org/articles/10.3389/fimmu.2017.01809/full

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We thought we’d share some brief highlights of Australian epigenetics publications over the last three months:

Extensive transcriptomic and epigenomic remodelling occurs during Arabidopsis thaliana germination

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

Epigenetic targeting of Notch1 driven transcription using the HDACi panobinostat is a potential therapy against T cell acute lymphoblastic leukemia

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.

https://www.nature.com/articles/leu2017282

Grandmaternal smoking increases asthma risk in grandchildren: a nationwide Swedish cohort

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.

https://doi.org/10.1111/cea.13031

H2A.Z and enhancers in prostate cancer

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.

Read more at garvan.org.au/news-events/news/how-genes-drive-prostate-cancer-all-in-the-packaging

https://www.nature.com/articles/s41467-017-01393-8

DNA methylation in blood from neonatal screening cards and the association with BMI and insulin sensitivity in early childhood

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.

https://www.nature.com/articles/ijo2017228

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Some highlights of Australian epigenetics publications in June-July 2017:

Click chemistry enables preclinical evaluation of targeted epigenetic therapies

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.

Differential intron retention in Jumonji chromatin modifier genes is implicated in reptile temperature-dependent sex determination

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.

Review: DNA methylation and the preservation of cell identity

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.

Review: Challenges in defining the role of intron retention in normal biology and disease

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.

Review: Epigenetic modulation in cancer immunotherapy

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.

G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

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.

Germ line–inherited H3K27me3 restricts enhancer function during maternal-to-zygotic transition

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.

 – Do you have any research news you would like to share with AEpiA members? Please email us about any recent publications, awards or events!