Latest AEpiA news
Here are the latest highlights of Australian epigenetics publications between July-Sept 2018:
In this year’s September edition of Nature Structural and Molecular Biology, Associate Professor Marnie Blewitt’s laboratory revealed that the noncanonical SMC protein Smchd1 is a novel regulator of long-range chromatin interactions in mice. The study, conducted primarily at the Walter and Eliza Hall Institute of Medical Research in Melbourne, tested the role of Smchd1 in maintaining chromosome structure using in situ Hi-C in Smchd1 depleted female mice. In doing so the authors discovered a role for Smchd1 in regulating Hox clusters in particular – thus adding to the canon of proteins known to epigenetically regulate Hox gene silencing during development. The report focused on the effect of losing Smchd1-dependent chromatin interaction in the inactive X (Xi) chromosome. This showed an increase in X-linked chromatin interaction in the absence of Smchd1, without the expected increase in reactivation of genes from the Xi. Instead, the report reveals, “spreading of trimethylated histone H3K27 domain into regions not normally decorated by this mark” on Smchd1 depleted Xi. The authors conclude that Smchd1 is able to insulate chromatin to limit access to other chromatin-modifying proteins and thereby regulate long-range chromatin interactions, thus adding to our understanding of how chromatin architecture is regulated.
From Melbourne’s Murdoch Children’s Research Institute, Professor Richard Saffery and colleagues have published an investigation on naïve CD4+ T cell activation in a cohort of infants with egg allergy. The study design involved activating T cells from non-atopic (control) and atopic individuals under non-differentiating conditions, and then profiling DNA methylation, gene expression and cell proliferation in these cells. The authors gained insight into naïve T cell responsiveness to activation. Comparison between the two groups showed that infants with food allergies have gene dysregulation in their T cell activation pathways leading to poor lymphoproliferative responses. The study reveals that the suboptimal T cell responses are underpinned by “reduced expression of cell cycle–related targets of the E2F and MYC transcription factor networks, and remodeling of DNA methylation at metabolic (RPTOR, PIK3D, MAPK1, FOXO1) and inflammatory genes (ILIR, ILI8RAP, CD82)”. The pathway modifications by gene-environment interactions seen in food allergy are thereby connected to epigenetic dysregulation in the early stages of signal transduction from the T cell receptor complex.
This June, the journal non-coding RNA published a review by Professor John Mattick, who has recently moved from the Garvan Institute of Medical Research in Sydney to Genomics England in London. In the review titled ‘The State of Long Non-Coding RNA Biology,’ Professor Mattick states that long non-protein-coding RNAs (lncRNAs) “are still to be widely accepted as major players in gene regulation.” This, he asserts, is “despite well characterized examples, their scaling with developmental complexity, and many demonstrations of their association with cellular process, development and diseases.” The review shines the spotlight on lncRNAs, starting with the history of their discovery and continuing to go into detail of the structure-function relationships of IncRNAs, which the review claims is “the most pressing challenge” to resolving the IncRNAs functional repertoire. The review ends by making the statement that RNA is “not (simply) . . . a transient intermediate between gene and protein, but rather the central computational engine of cell biology, differentiation and development, brain function and perhaps even evolution itself” and predicting that “many textbooks may have to be rewritten once the full dimensions of regulatory RNA biology are revealed.”
This study, led by Associate Professor Lee Wong at Monash University in Melbourne, reveals that oncogenic histone point mutations can “exert their effect through interaction with a range of epigenetic readers, writers and erasers”. Looking at the G34R (glycine to arginine) substitution mutation in the histone variant H3.3, the authors report downstream widespread changes in H3K9me3 and H3K36me3. The H3.3 G34R mutation is found in paediatric gliomas and the authors unravel that the changes to H3K9me3 and H3K36me3 are because H3.3 G34R is able to bind the demethylase KDM4 and inhibit its enzymatic activity. Inhibition of KDM4 activity in this way then affects H3K9me3 and H3K36me3 activity. Indeed the H3K9me3 and H3K36me3 profile in H3.3 G34R mutants in mouse embryonic stem cells is shown to be similar to KDM4 A/B/C triple-knock down. Thus, the study identifies the KDM4 histone lysine demethylases as “the key chromatin modifiers, which are disrupted by this mutant histone” and demonstrates how histone point mutation in cancer may exert their effects by interacting with epigenetic readers, writers and erasers.
From Melbourne’s Monash University, this study delves into transcriptional downregulation caused by intronic triple expansions. Expansion of trinucleotide repeats in intronic regions, as seen in diseases such as Friedreich’s ataxia and fragile X, can be expansive, with the possibility of up to 2,000 repeats. How these repeats lead to reduction in certain protein expression in these diseases was the interrogated question. Led by Associate Professor Sureshkumar Balasubramanian and published in Cell in August this year, the report revealed that: “triple repeat expansions can lead to local siRNA biogenesis, which in turn down regulates transcription”. The study goes on to show that this deregulation is mediated by RNA-dependent DNA methylation (RdDM) epigenetic modifications. Using an IIL1 repeat expansion in Arabidposis Thaliana, the authors unravel this molecular mechanism for the transcriptional downregulation in Arabidopsis. The report points to the need to assess RNA-dependent transcriptional gene silencing pathways to further understand the epigenetic attenuation of protein expression, particularly for disease conditions such as Friedreich’s ataxia.
The Epigenetics Consortium of South Australia Incorporated (EpiCSA) held its 3rd Annual Research Meeting on Wednesday 3 October 2018 at the South Australian Health and Medical Research Institute (SAHMRI) Auditorium.
The meeting was well attended and had 13 oral presentations and short talks by speakers from SA’s major research institutions. The keynote speaker was Dr Ozren Bogdanovic from the Garvan Institute of Medical Research in Sydney.
Ozren Bogdanovic presenting the keynote address at EpiCSA 2018 meeting
EpiCSA is very grateful to its wonderful sponsors, who helped keep the registration costs to a minimum and to award four prizes totalling $1000. Thank you to the University of Adelaide, CSIRO, NuGEN, Millenium Science, Genesearch, AGRF and Berrigan Wines.
The winner of the University of Adelaide Best Oral Presentation was Dexter Chan for his presentation on microRNAs in pregnancy.
Clara Pribadi won the CSIRO Best Short Talk Award for histone demethylase as a therapeutic target for craniosynostosis.
The attendees voted for the AGRF People’s Choice Award, which went to Melanie Smith for her work on microRNA profiling in the placenta.
The EpiCSA EPIC Award winner, who will be invited to give a talk at the 2019 meeting, was Michelle Forgione who is working on SNPs in epigenetic genes in Acute Lymphoblastic Leukemia (ALL). Congratulations Michelle!
The day was a huge success with lots of time for networking and discussing epigenetics, forming new collaborations and fostering old ones. Most importantly, the event would not have been possible without the EpiCSA committee members, our generous sponsors and EpiCSA members. The committee is already planning next year’s event, so watch this space!
Thanks to our sponsors:
Here are some highlights of Australian epigenetics publications that came out between April and July 2018:
From Sydney’s Garvan Institute of Medical Research and Melbourne’s Monash University, this study delves into the epigenetic differences between cancer-associated fibroblasts (CAFs) from localised prostate cancer and non-malignant prostate fibroblasts (NPFs). The study led by Professor Susan Clark investigated the cells in the microenvironment surrounding prostate cancer and found that cancer associated fibroblasts, CAFs, from the tumour microenvironment showed “distinct and enduring genome-wide changes in DNA methylation, compared to nonmalignant prostate fibroblasts”. Whole genome epigenetic analysis showed that these differences are found at enhancers and promoters of these fibroblasts. When coupled with transcriptome analysis, these methylation differences were seen to be associated with changes in gene expression related to cancer. The authors propose that the distinctions in the methylomes of cancer-associated and nonmalignant fibroblasts “promises new biomarkers to improve interpretation of diagnostic samples.”
For the full-text article: https://genome.cshlp.org/content/28/5/625.long
Professor Ryan Lister and team at the Harry Perkins Institute of Medical Research in Perth, describe an investigation into the acquisition of methyltransferases (DNMTs) by transposable elements. In the battle between transposable elements and host organisms, one ancient host mechanism for silencing transposons is via DNA methylation of transposons by DNMTs. This study characterised a wily counter attack acquired by transposable elements by describing how “two distantly related eukaryotic lineages, dinoflagellates and charophytes, have independently incorporated DNA methyltransferases into the coding regions of distinct retrotransposon classes.” Published in this years’ April edition of Nature Communications, the study further uncovered a novel methylation pattern in dinoflagellates of the genus Symbiodinium, where most of the genome is methylated at CG dinucleotides, unlike in any other eukaryote. The authors also report the discovery that retrotransposon DNA methyltransferases are able to methylate CGs de novo. This publication thus gives insight into the exciting and newly discovered event of cytosine-specific DNMT acquisition by eukaryotic retrotransposons and goes on to “assess their functional activity and profile the epigenomic characteristics of their algal hosts.”
For the full-text article: https://www.nature.com/articles/s41467-018-03724-9
This June, Human Molecular Genetics published a report entitled “Genome-wide survey of parent-of-origin effects on DNA methylation identifies candidate imprinted loci in humans”. This study was a collaborative effort from Queensland, led by Professor David Evans from The University of Queensland Diamantina Institute. The study delved into the mysteries of genomic imprinting in order to identify candidate imprinted loci. For this, the authors “leveraged” genome-wide DNA methylation from blood at three time-points (birth, childhood and adolescence) with genome-wide association studies (GWAS) data in 740 mother-child duos (from the Avon Longitudinal Study of parents and children). The project was based around the hypothesis that “cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions.” Using this approach the researchers identified genome-wide cis-meQTLs that exhibited parent-of-origin effects at 82 loci. By combining genetic and methylation data the researchers demonstrated that “parental allelic transmissions could be modelled at many imprinted (and linked) loci in GWAS of unrelated individuals”. The report expands on our understanding of human imprinting where the precise number of imprinted regions is still uncertain.
For the full-text article: https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddy206/5026426
This report led by Professor Susan Clark and team at Garvan Institute of Medical Research in Sydney provides an optimized WGBS methodology for both high-quality intact DNA and degraded DNA from formalin-fixed paraffin-embedded tissue, on the HiSeq X Ten platform. The study provides a complete protocol from library preparation to sequencing and data processing, “to enable 16–20× genome-wide coverage per single lane”, thus enabling larger-scale population based WGBS studies to be more cost-effective. The samples were analysed using the newly developed WGBS pipeline (METH10X), which allows fast data processing and also has the SNP calling algorithm embedded in the pipeline. The authors further performed integrated whole genome sequencing (WGS) and WGBS of the same DNA sample in a single lane of HiSeq X Ten, thus paving the way towards an efficient and cost-effective method to explore combinatorial anlaysis of genetic and epigenetic variations on one common sequencing platform.
For the full-text article:https://epigeneticsandchromatin.biomedcentral.com/articles/10.1186/s13072-018-0194-0
Published in Genome Research in advance this June, Professor Ryan Lister’s team at the Harry Perkins Institute of Medical Research, The University of Western Australia, reveals a modular dCas9-SunTag DNMT3A system that “enables precise DNA methylation deposition with the lowest amount of off-target DNA methylation reported to date”. In an effort to improve on the current tools for altering DNA methylation at desired loci, Pflueger et al have adapted DNA methyl transferase (DNMT) genome editing technologies and added a modular dCas9-SunTag (dC9Sun-D3A) system “that can recruit multiple DNMT3A catalytic domains to a target site for editing DNA methylation”. The authors show that by addition of this tag the DNMT3A construct becomes “tunable, specific and exhibits much higher induction of DNA methylation at target sites” than the previously available dC9-D3A direct fusion protein. This new tool will enable more accurate methylation editing and therefore “more accurate functional determination of the role of DNA methylation at single loci”.
For the article: https://www.ncbi.nlm.nih.gov/pubmed/29907613
From Adelaide’s South Australian Health & Medical Research Institute, Professor Deborah White and colleagues have reviewed the benefits of precision medicine in Down Syndrome (DS) patients with Acute Lymphoblastic Leukemia (ALL). Children with DS have a 20-fold increased risk of developing ALL, and Page et al. discussed the need to address ALL in these individuals due to the “poorer survival outcomes and higher treatment related toxicity” of DS children compared to non-DS-ALL patients. The authors find that since common genomic alterations observed in non-DS-ALL patients do not occur frequently in DS patients, therapies targeting such alterations are not often suitable for DS patients. The review points out that in individuals with DS, higher-risk fusions usually associated with a more aggressive leukaemia phenotype, are often observed, and suggests that this incongruence between DS-ALL and non-DS-ALL “may contribute to the higher rate of relapse in DS-ALL compared to non-DS-ALL patients”. The authors conclude that a deeper understanding of the genomic landscape of DS-ALL patients is needed, including an understanding of epigenetic alterations, which are not well characterised to date, but are likely involved in the observed gene fusions. Subsequent investigation of targeted therapies for DS-ALL may provide ways to reduce the toxic chemotherapeutic effects of current treatment on DS-ALL patients.
For the full-text article: https://www.cancerletters.info/article/S0304-3835(18)30384-7/fulltext