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.
Australia, The University of Sydney, BSc (Hons), PhD
2020 Genetics Society of AustralAsia Ross Crozier Medal
2017 Bellberry-Viertel Senior Medical Research Fellowship
2015 Lorne Genome Women in Science Award
2013 Financial Review Top 100 Women of Influence Award
2009 L’Oreal Australia For Women in Science Fellowship
2009 Australian Academy of Science Ruth Stephens Gani Medal, for human genetics
2020-2024 National Health and Medical Research Council L1 Investigator grant
2020 – 2024 Pamela and Lorenzo Galli Foundation funding
2019-2024 Foundation for Prader Willi USA funding
2017-2023 Prader Willi Research Foundation Australia project funding
2017-2023 FSHD Global therapeutics funding
Associate editor, Biochemical Society Transactions, 2018 ongoing
Associate editor, PLoS Genetics, 2021 ongoing
Coursera online course on Epigenetic control of gene expression, 2012 ongoing
N Benetti, Q Gouil, A Tapia Del Fierro, T Beck, K Breslin, A Keniry, E McGlinn*, ME BLEWITT*. Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo. NATURE COMMUNICATIONS. 2022 Jul 25;13(1):4295.
A Keniry*, N Jansz, PF Hickey, K Breslin, M Iminitoff, T Beck, QA Gouil, ME Ritchie, ME BLEWITT*. A method for stabilising the XX karyotype in female mESC cultures. DEVELOPMENT 2022 Nov 15;149(22)
A Keniry*, N Jansz, LJ Gearing, I Wanigasuriya, J Chen, CM Nefzger, PF Hickey, Q Gouil, J Liu, KA Breslin, M Iminitoff, T Beck, A Tapia del Fierro, L Whitehead, A Jarratt, SA Kinkel, PC Taberlay, T Willson, M Pakusch, ME Ritchie, DJ Hilton, JM Polo, ME BLEWITT* Xmas mESC: A female embryonic stem cell system that reveals the BAF complex as a key regulator of establishment of X chromosome inactivation. NATURE COMMUNICATIONS 2022 Mar 29;13(1):1658
I Wanigasuriya*, QA Gouil*, SA Kinkel, A Tapia Del Fierro, T Beck, EA Roper, K Breslin, J Stringer, K Hutt, HJ Lee, A Keniry, ME Ritchie, ME BLEWITT. Smchd1 is a maternal effect gene required for genomic imprinting. eLIFE 2020 Nov 13;9:e55529
N Jansz, T Nesterova, A Keniry, M Iminitoff, PF Hickey, G Pintacuda, O Masui, S Kolbeke, N Geoghegan, KA Breslin, TA Willson, K Rogers, GF Kay, AH Fox, H Koseki, N Brockdorff, JM Murphy, ME BLEWITT. Smchd1 targeting to the inactive X is dependent on the Xist-HnrnpK-PRC1 pathway. CELL REPORTS 2018 Nov 1;25(7):1912-192
N Jansz, A Keniry, M Trussart, H. Bildsoe, T. Beck, ID Tonks, AW Mould, P Hickey, K Breslin, M Iminitoff, ME Ritchie, E McGlinn, GF Kay, JM Murphy and ME Blewitt Smchd1 regulates long-range chromatin interactions on the inactive X chromosome and at Hox clusters. NAT STRUCT MOL BIOL 2018 25, 766-777
CT Gordon^, S Xue^, G Yigit^, H Filali^, K Chen^, N Rosin, KI Yoshiura, M Oufadem, TJ Beck, R McGowan, AC Magee, J Altmüller, C Dion, H Thiele, AD Gurzau, … JM Murphy, C Chatdokmaiprai, AM Hillmer, D Wattanasirichaigoon, S Lyonnet, F Magdinier, A Javed*, ME BLEWITT*, J Amiel*, B Wollnik*, B Reversade* De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. NATURE GENETICS 2017 Feb;49(2):249-255
K Chen, J Hu, DL Moore, R Liu, SA Kessans, K Breslin, IS Lucet, A Keniry, HS Leong, CL Parish, DJ Hilton, RJ Lemmers, SM van der Maarel, PE Czabotar, RC Dobson, ME Ritchie, GF Kay*, JM Murphy*, ME BLEWITT* Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. PROC NATL ACAD SCI USA 2015 Jul 7;112(27):55-44
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.
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.
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.
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.