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We thought we’d share some brief highlights of Australian epigenetics publications from the beginning of this year (2018):

The Tumor Suppressor Hic1 Maintains Chromosomal Stability Independent of Tp53

In a brief communication to Oncogene, this January, Professor Watkins from the Garvan Institute of Medical Research, Sydney and colleagues from Monash University, Melbourne used a conditional knockout mouse model to inactivate Hypermethylated–in-Cancer1 (Hic1) tumour suppressor gene. Using this model, Szczepny et al., show that the knockout mouse phenocopies a Brca1 deletion. The knockout resulted in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. The study reveals that Hic1, which is inactivated by epigenetic silencing in many cancers, “may contribute to malignant transformation through the acquisition of chromosomal instability”, when expression is lost in early tumour formation.

For full-text by Szczepny et al., see – doi 10.1038/s41388-017-0022-1

DNA Methylation-Based Biological Ageing and Cancer Risk and Survival: Pooled Analysis of Seven Prospective Studies

In this publication, Dr Pierre-Antoine Dugué et al., from Cancer Council Victoria, and The University of Melbourne utilize the Melbourne Collaborative Cohort Study to look for an association between ageing and cancer. For this, the authors compared ‘age acceleration’, against the risk of and survival from colorectal, gastric, kidney, lung, prostate, urothelial cancer and B‐cell lymphoma. Age acceleration is a measure of biological ageing based on DNA methylation. Based on their analysis the study was able to identify that “DNA methylation-based measures of biological ageing are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors”. Further, the study found that this was consistent across cancer types. As blood samples were obtained from participants prior to cancer diagnosis, the findings add evidence to the use of “methylation markers of biological ageing as putative predictors of health outcomes”.

For full-text by Dugué et al., see – https://doi.org/10.1186/s13059-017-1302-3

DUSP5 is Methylated in CIMP-high Colorectal Cancer but is Not a Major Regulator of Intestinal Cell Proliferation and Tumorigenesis

Based on their finding that the nuclear ERK-selective phosphatase DUSP5 is downregulated in colorectal tumours and cell lines Togel et al., investigate epigenetic changes to the DUSP5 promoter. The study finds that indeed a subset of DUSP5 promoters are methylated in colorectal cancer (CRC) cell lines and tumours. This promoter methylation is reported to be present particularly in CRCs with the CpG island methylator phenotype (CIMP), which is used for diagnostic, prognostic and monitoring purposes. The study by Professor Mariadason and colleagues from the Olivia Newton-John Cancer Research Institute, and Ludwig Institute for Cancer Research in Melbourne concludes that this epigenetic change “could not account for reduced DUSP5 expression”, but it “can serve as an additional means of identifying CIMP-high colorectal cancer”.

For the full-text article by Tögel et al., see – DOI: 0.1038/s41598-018-20176-9

Epigenome-Wide Analysis in Newborn Blood Spots from Monozygotic Twins Discordant for Cerebral Palsy Reveals Consistent Regional Differences in DNA Methylation

From the Murdoch Children’s Research Institute, Melbourne and the Department of Paediatrics at The University of Melbourne, Mohandas et al., utilise the discordant monozygotic twin model to understand and measure epigenetic changes associated with the development of Cerebral palsy. The study led by A/Professor Craig used Illumina Infinium Human Methylation 450 BeadChip arrays on DNA from 15 newborn monozygotic twin pairs. These twins later became discordant for Cerebral palsy. Their results revealed 33 differentially methylated probes related 2 Differentially Methylated Regions (DMRs) making “an initial step towards investigating potential CP-associated epigenetic differences, with the longer term aim of identifying predictive biomarkers with clinical utility.”

For the full-text article by Mohandas et al., DOI: 10.1186/s13148-018-0457-4

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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

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