Dr Marnie Blewitt

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Division: Molecular Medicine

Research Overview

The genome contains all of the information required to form the vast array of cell types found in an adult human, with their multitude of disparate functions. How is it that the same genetic information can lead to so many different functional outcomes? We now understand that cellular differentiation is achieved by expression of only a subset of genes within each cell type, enabled by epigenetic modifications made to the chromatin. Epigenetic modifications include DNA methylation, post-translational modification of the histone proteins that package the DNA, use of histone variants, and small interfering RNAs, and in total they relate to the likelihood that a particular gene will be expressed. Tight epigenetic control is important not only for cellular differentiation, but also to maintain an undifferentiated state in stem cell populations. Perhaps, as you might expect for such a ubiquitously important process, aberrant epigenetic regulation both during embryonic development and in the adult is associated with myriad diseases, for example cancer.

Our primary interest is in understanding the molecular mechanisms behind the epigenetic control of gene expression. We use several model systems to study the interaction between known and novel epigenetic modifiers: X inactivation, haematopoietic stem cell activity and cancer. In each case, we are interested in how epigenetic modifiers are able to elicit transcriptional silencing or activation, and in turn how this relates to the functional outcomes for the cell. We use a combination of genetic and genomic techniques to address these questions, including mutant, knockout and genetrap alleles, in vivo shRNA mediated knockdown, chromatin immunoprecipitation followed by NextGen sequencing and microarray expression analysis. By studying the molecular mechanisms that govern epigenetic control in normal development in the long term we hope to understand more about how it goes awry in disease, and therefore how we may manipulate epigenetic state for therapeutic gain.

Research Interests

Selected Publications

  1. Blewitt ME, Gendrel A-V, Pang Z, Sparrow DB, Whitelaw N, Craig J, Apedaile A, Hilton DJ, Dunwoodie SL, Brockdorff N, Kay GK and Whitelaw E (2008) SmcHD1, a protein containing a structural maintenance of chromosomes hinge domain, has a critical role in X inactivation. Nat Genet May; 40(5):663-9. PMID: 18425126
  2. Majewski IJ, Blewitt M, deGraaf C, McManus E, Bahlo M, Hyland C, Smyth GK, Corbin J, Metcalf D, Alexander WS, and Hilton DJ (2008) Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell identity. PLoS Biology Apr 15; 6(4):e93. PMID: 18416604
  3. Blewitt ME, Vickaryous NK, Hemley SJ, Ashe A, Bruxner TJ, Preis JI, Arkell R and Whitelaw E (2005) An ENU screen for genes involved in variegation in the mouse. Proc Natl Acad Sci U S A 102(21): 7629-7634. PMID: 15890782
  4. Ashe A, Morgan DK, Whitelaw NC, Bruxner TJ, Vickaryous NK, Cox LL, Butterfield NC, Wicking C, Blewitt ME, Wilkins S, Anderson G, Cox TX and Whitelaw E. (2008) A genome-wide screen for modifiers of transgene variegation identifies genes with critical roles in development. Genome Biol Vol 9 (12) R182 PMID: 19099580
  5. Chong S, Vickaryous N, Ashe A, Zamudio N, Youngson N, Hemley S, Stopka T, Skoultchi A, Matthews J, Scott H, de Kretser D, O’Bryan M, Blewitt M and Whitelaw E (2007) Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet 2007 May;39(5):614-22. Epub 2007 Apr 22. PMID: 17450140
  6. Blewitt ME, Vickaryous NK, Paldi A Koseki H and Whitelaw E (2006) Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genetics April 2(4) e49. PMID: 16604157
  7. Rakyan VK, Chong S, Champ ME, Cuthbert PC, Morgan HD, Luu KVK and Whitelaw E (2003) Transgenerational inheritance of epigenetic states at the murine AxinFu allele occurs following maternal and paternal transmission. Proc Natl Acad Sci U S A 100(5): 2538-43 PMID: 12601169

Reviews:

  1. Blewitt ME, Chong S and Whitelaw E (2004) How the mouse got its spots. Trends in Genetics 20(11): 550-554. PMID: 15475114
  2. Rakyan VK, Blewitt ME, Druker R, Preis JI and Whitelaw E (2002) Metastable epialleles in mammals. Trends in Genetics 18(7): 348-351. PMID: 12127774

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Current Laboratory Members

Faculty Member: Marnie Blewitt BSc (Hons) PhD Syd

Postdoctoral Fellow: Sarah Kinkel BA BSc (Hons) Melb

Postdoctoral Fellow: Andrew Keniry, BSc Melb, PhD Cambridge

Research Assistant: Kelsey Breslin, BSc(Hons) Alberta

Research Assistant: Miha Pakusch BSc (Hons) Melb

Postgraduate Student: Linden (Jamie) Gearing BSc (Hons) Melb

Postgraduate Student: Darcy Butts BSc Michigan MSc Oxford

Postgraduate Student: Kelan Chen BSc Melb

Scientific Coordinator/Alliance Manager: Fiona McGrath BAppSc(Hons) RMIT

Administration Officer: Etty Bonnici