Prof Marnie Blewitt, Deputy Director | WEHI Researcher Profile

Q: Screening for novel epigenetic modifiers using X inactivation as a model system

A major stumbling block to understanding epigenetic control is that we do not know the identity of all of the factors involved in epigenetic control, and therefore our understanding of the molecular mechanisms of epigenetic control will necessarily be incomplete. We are performing in vitro screens to identify new roles for known players plus uncharacterised epigenetic modifiers. Our screen utilises novel Xmas ES cells to rapidly analyse X inactivation, as a model epigenetic system. Positive hits are characterised for their role in X inactivation, and more broadly studied in pluripotency, development and disease.Project links:https://www.wehi.edu.au/news/dna-discovery-reveals-critical-accordion-effect-switching-genes

Q: Characterizing the molecular function of SMCHD1

SMCHD1 is an epigenetic regulator important for silencing the inactive X chromosome in females plus a series of autosomal clustered gene families, such as the Hox genes, imprinted genes and the D4Z4 macrosatellite repeat in humans. We are studying how SMCHD1 functions at the chromatin using genomic technologies, dynamic imaging, biochemical and biophysical assays, structural biology approaches to reveal how it is able to perform its role to switch genes off.Project link:https://www.wehi.edu.au/news/dna-discovery-reveals-critical-accordion-effect-switching-genes

Q: Testing whether targeting SMCHD1 is relevant in the context of disease

Based on SMCHD1's known target genes, it may be relevant to inhibit or activate SMCHD1 function in the context of disease, namely imprinting disorder Prader Willi syndrome for the former and muscular dystrophy FSHD for the latter. We are performing proof-of-principle studies in patient-derived iPSC model systems and living models to test whether this is the case. This work complements our active drug discovery programs.Project links:https://www.wehi.edu.au/news/four-new-projects-announced-national-drug-discovery-centrehttps://www.wehi.edu.au/news/waking-sleeping-genes-could-help-prader-willi-syndromehttps://www.wehi.edu.au/news/gene-discovery-could-prevent-onset-muscular-dystrophy

Q: Targeting chromatin to treat neurodevelopmental disorders

Based on the effective treatment of inborn errors of metabolism that cause intellectual disability with interventions during infancy when brain development is ongoing, we are now investigating whether the same might be true in neurodevelopmental disorders with a basis in chromatin dysfunction. We are modelling several neurodevelopmental syndromes, seeking to understand their molecular underpinnings to then design treatments that may correct the alteration to treat disease.

About

We aim to understand the molecular mechanisms behind epigenetic silencing. We use several model systems to study the interaction between known and novel epigenetic modifiers: X inactivation, genomic imprinting, and embryonic development.

In each case, we seek to understand how epigenetic modifiers elicit transcriptional silencing, and how this relates to functional outcomes for the cell. We use a combination of genetic, genomic and advanced imaging techniques to address these questions.

By studying the molecular mechanisms governing epigenetic control in normal development, we hope to understand how it goes awry in disease. This may reveal how we can manipulate epigenetic state for therapeutic gain.

Our current focus is the epigenetic regulator SMCHD1. We are screening for small molecule activators and inhibitors of SMCHD1: the former as potential treatments for facioscapulohumeral muscular dystrophy, the latter for Prader Willi and Schaaf-Yang syndromes. These diseases have no current targeted treatments and remain incurable.

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Selected publications from Prof Marnie Blewitt

Tan W, Park J, Venugopal H, Lou J, Dias PS, Baldoni PL, Moon K-W, Dite TA, Keenan CR, Gurzau AD, Lee J, Johanson TM, Leis A, Yousef J, Vaibhav V, Dagley LF, Ang C-S, Corso LD, Davidovich C, Vervoort SJ, Smyth GK, Blewitt ME, Allan RS, Hinde E, D’Arcy S, Ryu J-K, Shakeel S. MORC2 is a phosphorylation-dependent DNA compaction machine. Nature Communications. 2025;16(1):10.1038/s41467-025-60751-z

Bergamasco MI, Ozturk E, Casillas-Espinosa PM, Garnham AL, Abeysekera W, Wimmer VC, Rajasekhar P, Vanyai HK, Whitehead L, Blewitt ME, Rogers K, Vogel AP, Hannan AJ, Smyth GK, Jones NC, Thomas T, Voss AK. KAT6B overexpression in mice causes aggression, anxiety, and epilepsy. iScience. 2025;28(3):10.1016/j.isci.2025.111953

Gocuk SA, Lancaster J, Su S, Jolly JK, Edwards TL, Hickey DG, Ritchie ME, Blewitt ME, Ayton LN, Gouil Q. Measuring X-Chromosome inactivation skew for X-linked diseases with adaptive nanopore sequencing. Genome Research. 2024;34(11):10.1101/gr.279396.124

Bennett C, Pettikiriarachchi A, McLean ARD, Harding R, Blewitt ME, Seillet C, Pasricha S. Serum iron and transferrin saturation variation are circadian regulated and linked to the harmonic circadian oscillations of erythropoiesis and hepatic Tfrc expression in mice. American Journal of Hematology. 2024;99(11):10.1002/ajh.27447

Short KM, Tortelote GG, Jones LK, Diniz F, Edgington-Giordano F, Cullen-McEwen LA, Schröder J, Spencer A, Keniry A, Polo JM, Bertram JF, Blewitt ME, Smyth IM, El-Dahr SS. The Impact of Low Protein Diet on the Molecular and Cellular Development of the Fetal Kidney. 2024;4(12-15):10.1101/2023.12.04.569988

Bergamasco MI, Vanyai HK, Garnham AL, Geoghegan ND, Vogel AP, Eccles S, Rogers KL, Smyth GK, Blewitt ME, Hannan AJ, Thomas T, Voss AK. Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice. Journal of Clinical Investigation. 2024;134(7):10.1172/jci167672

Keenan CR, Coughlan HD, Iannarella N, del Fierro AT, Keniry A, Johanson TM, Chan F, Garnham AL, Whitehead LW, Blewitt ME, Smyth GK, Allan RS. Suv39h-catalyzed H3K9me3 is critical for euchromatic genome organization and the maintenance of gene transcription. Genome Research. 2024;34(4):10.1101/gr.279119.124

Blewitt ME. Mary Lyon and the birth of X-inactivation research. Nature Reviews Genetics. 2024;25(1):10.1038/s41576-023-00655-0

Su S, Xiao L, Lancaster J, Cameron T, Breslin K, Hickey PF, Blewitt ME, Gouil Q, Ritchie ME. A streamlined workflow for long-read DNA methylation analysis with NanoMethViz and Bioconductor. F1000Research. 2024;13:10.12688/f1000research.155204.1

Su S, Xiao L, Lancaster J, Cameron T, Breslin K, Hickey PF, Blewitt ME, Gouil Q, Ritchie ME. A streamlined workflow for long-read DNA methylation analysis with NanoMethViz and Bioconductor. F1000Research. 2024;13:10.12688/f1000research.155204.2

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Screening for novel epigenetic modifiers using X inactivation as a model system

Characterizing the molecular function of SMCHD1

Testing whether targeting SMCHD1 is relevant in the context of disease

Targeting chromatin to treat neurodevelopmental disorders

Prof Marnie Blewitt

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