Natasha joined the Genome Plasticity and Disease group in January 2021 to study the mechanisms governing expression from proviral DNA. Natasha has a background in molecular epigenetics. She was awarded her PhD in the lab of Professor Marnie Blewitt, at WEHI in Melbourne, Australia in 2018. There, she characterised the structural maintenance of chromosomes protein, Smchd1, in mammalian development. Natasha was awarded a Humboldt Research Fellowship, HFSP Postdoctoral Fellowship, and an EMBO Postdoctoral Fellowship (non-stipendiary) to train at the Institute of Epigenetics and Stem Cells in Munich, Germany, where she studied transposable element function in preimplantation development. Natasha has joined the team of Professor Geoffrey Faulkner, supported by an NHMRC Investigator Grant, to investigate mechanisms underlying endogenous and exogenous retrovirus regulation in infectious and malignant disease.
Jansz, Natasha; Faulkner, Geoffrey J
Endogenous retroviruses in the origins and treatment of cancer (Journal Article)
In: Genome Biology, 22 (1), pp. 147, 2021, ISSN: 1474-760X.
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Endogenous retroviruses (ERVs) are emerging as promising therapeutic targets in cancer. As remnants of ancient retroviral infections, ERV-derived regulatory elements coordinate expression from gene networks, including those underpinning embryogenesis and immune cell function. ERV activation can promote an interferon response, a phenomenon termed viral mimicry. Although ERV expression is associated with cancer, and provisionally with autoimmune and neurodegenerative diseases, ERV-mediated inflammation is being explored as a way to sensitize tumors to immunotherapy. Here we review ERV co-option in development and innate immunity, the aberrant contribution of ERVs to tumorigenesis, and the wider biomedical potential of therapies directed at ERVs.
Jansz, Natasha; Torres-Padilla, Maria-Elena
Genome activation and architecture in the early mammalian embryo (Journal Article)
In: Current Opinion in Genetics & Development, 55 , pp. 52–58, 2019, ISSN: 0959-437X.
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Over the last decade, our understanding of how the genome is packaged in three dimension within the nucleus has grown considerably. This is largely due to advances in high-throughput genomics assays to study higher order chromatin organization. Our knowledge of the structures adopted by the chromatin has far preceded our understanding of function and mechanism. An outstanding question has been how are such structures established. Recently, a suite of genomics assays has been adapted for low-input material, making it possible to apply them to the pre-implantation mammalian embryo. For the first time, chromatin topology and associations with the nuclear lamina have been described in the earliest stages of murine development. These studies have revealed the dynamics with which higher-order chromatin architecture is established in vivo. Additionally, they have yielded some intriguing findings that will pave the way for futures studies into the mechanisms underlying the establishment of three dimensional genome organization. Here, we discuss findings on how embryonic chromatin is dynamically organized within the nucleus throughout preimplantation development, and the outline a number of outstanding questions that will be exciting to address in the future.
Delbridge, Alex R D; Kueh, Andrew J; Ke, Francine; Zamudio, Natasha M; El-Saafin, Farrah; Jansz, Natasha; Wang, Gao-Yuan; Iminitoff, Megan; Beck, Tamara; Haupt, Sue; Hu, Yifang; May, Rose E; Whitehead, Lachlan; Tai, Lin; Chiang, William; Herold, Marco J; Haupt, Ygal; Smyth, Gordon K; Thomas, Tim; Blewitt, Marnie E; Strasser, Andreas; Voss, Anne K
In: Cell Reports, 27 (2), pp. 442–454.e5, 2019, ISSN: 2211-1247.
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Neural tube defects (NTDs) are common birth defects in humans and show an unexplained female bias. Female mice lacking the tumor suppressor p53 display NTDs with incomplete penetrance. We found that the combined loss of pro-apoptotic BIM and p53 caused 100% penetrant, female-exclusive NTDs, which allowed us to investigate the female-specific functions of p53. We report that female p53−/− embryonic neural tube samples show fewer cells with inactive X chromosome markers Xist and H3K27me3 and a concomitant increase in biallelic expression of the X-linked genes, Huwe1 and Usp9x. Decreased Xist and increased X-linked gene expression was confirmed by RNA sequencing. Moreover, we found that p53 directly bound response elements in the X chromosome inactivation center (XIC). Together, these findings suggest p53 directly activates XIC genes, without which there is stochastic failure in X chromosome inactivation, and that X chromosome inactivation failure may underlie the female bias in neural tube closure defects.
DNA methylation dynamics at transposable elements in mammals (Journal Article)
In: Essays in Biochemistry, 63 (6), pp. 677–689, 2019, ISSN: 0071-1365.
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Transposable elements dominate the mammalian genome, but their contribution to genetic and epigenetic regulation has been largely overlooked. This was in part due to technical limitations, which made the study of repetitive sequences at single copy resolution difficult. The advancement of next-generation sequencing assays in the last decade has greatly enhanced our understanding of transposable element function. In some instances, specific transposable elements are thought to have been co-opted into regulatory roles during both mouse and human development, while in disease such regulatory potential can contribute to malignancy. DNA methylation is arguably the best characterised regulator of transposable element activity. DNA methylation is associated with transposable element repression, and acts to limit their genotoxic potential. In specific developmental contexts, erasure of DNA methylation is associated with a burst of transposable element expression. Developmental regulation of DNA methylation enables transposon activation, ensuring their survival and propagation throughout the host genome, and also allows the host access to regulatory sequences encoded within the elements. Here I discuss DNA methylation at transposable elements, describing its function and dynamic regulation throughout murine and human development.
Jansz, Natasha; Nesterova, Tatyana; Keniry, Andrew; Iminitoff, Megan; Hickey, Peter F; Pintacuda, Greta; Masui, Osamu; Kobelke, Simon; Geoghegan, Niall; Breslin, Kelsey A; Willson, Tracy A; Rogers, Kelly; Kay, Graham F; Fox, Archa H; Koseki, Haruhiko; Brockdorff, Neil; Murphy, James M; Blewitt, Marnie E
In: Cell Reports, 25 (7), pp. 1912–1923.e9, 2018, ISSN: 2211-1247.
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We and others have recently reported that the SMC protein Smchd1 is a regulator of chromosome conformation. Smchd1 is critical for the structure of the inactive X chromosome and at autosomal targets such as the Hox genes. However, it is unknown how Smchd1 is recruited to these sites. Here, we report that Smchd1 localizes to the inactive X via the Xist-HnrnpK-PRC1 (polycomb repressive complex 1) pathway. Contrary to previous reports, Smchd1 does not bind Xist or other RNA molecules with any specificity. Rather, the localization of Smchd1 to the inactive X is H2AK119ub dependent. Following perturbation of this interaction, Smchd1 is destabilized, which has consequences for gene silencing genome-wide. Our work adds Smchd1 to the PRC1 silencing pathway for X chromosome inactivation.
Jansz, Natasha; Keniry, Andrew; Trussart, Marie; Bildsoe, Heidi; Beck, Tamara; Tonks, Ian D; Mould, Arne W; Hickey, Peter; Breslin, Kelsey; Iminitoff, Megan; Ritchie, Matthew E; McGlinn, Edwina; Kay, Graham F; Murphy, James M; Blewitt, Marnie E
In: Nature Structural & Molecular Biology, 25 (9), pp. 766–777, 2018, ISSN: 1545-9985, (Bandiera_abtest: a Cg_type: Nature Research Journals Number: 9 Primary_atype: Research Publisher: Nature Publishing Group Subject_term: Chromatin structure;Dosage compensation;Epigenomics;Gene silencing Subject_term_id: chromatin-structure;dosage-compensation;epigenomics;gene-silencing).
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The regulation of higher-order chromatin structure is complex and dynamic, and a full understanding of the suite of mechanisms governing this architecture is lacking. Here, we reveal the noncanonical SMC protein Smchd1 to be a novel regulator of long-range chromatin interactions in mice, and we add Smchd1 to the canon of epigenetic proteins required for Hox-gene regulation. The effect of losing Smchd1-dependent chromatin interactions has varying outcomes that depend on chromatin context. At autosomal targets transcriptionally sensitive to Smchd1 deletion, we found increased short-range interactions and ectopic enhancer activation. In contrast, the inactive X chromosome was transcriptionally refractive to Smchd1 ablation, despite chromosome-wide increases in short-range interactions. In the inactive X, we observed spreading of trimethylated histone H3 K27 (H3K27me3) domains into regions not normally decorated by this mark. Together, these data suggest that Smchd1 is able to insulate chromatin, thereby limiting access to other chromatin-modifying proteins.
Liu, Xiaodong; Nefzger, Christian M; Rossello, Fernando J; Chen, Joseph; Knaupp, Anja S; Firas, Jaber; Ford, Ethan; Pflueger, Jahnvi; Paynter, Jacob M; Chy, Hun S; O'Brien, Carmel M; Huang, Cheng; Mishra, Ketan; Hodgson-Garms, Margeaux; Jansz, Natasha; Williams, Sarah M; Blewitt, Marnie E; Nilsson, Susan K; Schittenhelm, Ralf B; Laslett, Andrew L; Lister, Ryan; Polo, Jose M
In: Nature Methods, 14 (11), pp. 1055–1062, 2017, ISSN: 1548-7105, (Bandiera_abtest: a Cg_type: Nature Research Journals Number: 11 Primary_atype: Research Publisher: Nature Publishing Group Subject_term: Biological models;Embryonic stem cells;Pluripotent stem cells;Reprogramming Subject_term_id: biological-models;embryonic-stem-cells;pluripotent-stem-cells;reprogramming).
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This study compares naive human pluripotent stem cells, either reprogrammed directly from somatic cells or converted from primed cells, under a variety of culture conditions.
Jansz, Natasha; Chen, Kelan; Murphy, James M; Blewitt, Marnie E
The Epigenetic Regulator SMCHD1 in Development and Disease (Journal Article)
In: Trends in Genetics, 33 (4), pp. 233–243, 2017, ISSN: 0168-9525.
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It has very recently become clear that the epigenetic modifier SMCHD1 has a role in two distinct disorders: facioscapulohumoral muscular dystrophy (FSHD) and Bosma arhinia and micropthalmia (BAMS). In the former there are heterozygous loss-of-function mutations, while both gain- and loss-of-function mutations have been proposed to underlie the latter. These findings have led to much interest in SMCHD1 and how it works at the molecular level. We summarise here current understanding of the mechanism of action of SMCHD1, its role in these diseases, and what has been learnt from study of mouse models null for Smchd1 in the decade since the discovery of SMCHD1.
Keniry, Andrew; Gearing, Linden J; Jansz, Natasha; Liu, Joy; Holik, Aliaksei Z; Hickey, Peter F; Kinkel, Sarah A; Moore, Darcy L; Breslin, Kelsey; Chen, Kelan; Liu, Ruijie; Phillips, Catherine; Pakusch, Miha; Biben, Christine; Sheridan, Julie M; Kile, Benjamin T; Carmichael, Catherine; Ritchie, Matthew E; Hilton, Douglas J; Blewitt, Marnie E
In: Epigenetics & Chromatin, 9 (1), pp. 16, 2016, ISSN: 1756-8935.
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The presence of histone 3 lysine 9 (H3K9) methylation on the mouse inactive X chromosome has been controversial over the last 15 years, and the functional role of H3K9 methylation in X chromosome inactivation in any species has remained largely unexplored.
Liu, Ruijie; Chen, Kelan; Jansz, Natasha; Blewitt, Marnie E; Ritchie, Matthew E
Transcriptional profiling of the epigenetic regulator Smchd1 (Journal Article)
In: Genomics Data, 7 , pp. 144–147, 2016, ISSN: 2213-5960.
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Smchd1 is an epigenetic repressor with important functions in healthy cellular processes and disease. To elucidate its role in transcriptional regulation, we performed two independent genome-wide RNA-sequencing studies comparing wild-type and Smchd1 null samples in neural stem cells and lymphoma cell lines. Using an R-based analysis pipeline that accommodates observational and sample-specific weights in the linear modeling, we identify key genes dysregulated by Smchd1 deletion such as clustered protocadherins in the neural stem cells and imprinted genes in both experiments. Here we provide a detailed description of this analysis, from quality control to read mapping and differential expression analysis. These data sets are publicly available from the Gene Expression Omnibus database (accession numbers GSE64099 and GSE65747).
Liu, Ruijie; Holik, Aliaksei Z; Su, Shian; Jansz, Natasha; Chen, Kelan; Leong, Huei San; Blewitt, Marnie E; Asselin-Labat, Marie-Liesse; Smyth, Gordon K; Ritchie, Matthew E
In: Nucleic Acids Research, 43 (15), pp. e97–e97, 2015, ISSN: 0305-1048.
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Variations in sample quality are frequently encountered in small RNA-sequencing experiments, and pose a major challenge in a differential expression analysis. Removal of high variation samples reduces noise, but at a cost of reducing power, thus limiting our ability to detect biologically meaningful changes. Similarly, retaining these samples in the analysis may not reveal any statistically significant changes due to the higher noise level. A compromise is to use all available data, but to down-weight the observations from more variable samples. We describe a statistical approach that facilitates this by modelling heterogeneity at both the sample and observational levels as part of the differential expression analysis. At the sample level this is achieved by fitting a log-linear variance model that includes common sample-specific or group-specific parameters that are shared between genes. The estimated sample variance factors are then converted to weights and combined with observational level weights obtained from the mean–variance relationship of the log-counts-per-million using ‘voom’. A comprehensive analysis involving both simulations and experimental RNA-sequencing data demonstrates that this strategy leads to a universally more powerful analysis and fewer false discoveries when compared to conventional approaches. This methodology has wide application and is implemented in the open-source ‘limma’ package.
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