|Postdoc Fellow-Stem Cell and Cancer Epigenetics
|Date Posted||Thursday, 11 October 2012|
|Location||King's College London|
King's College London
123 Coldharbour Lane
Denmark Hill, London, SE5 9NU
|Job Description||This post is within the Leukaemia and Stem Cell Biology Group led by Professor So. The group is working on transcriptional deregulation and self-renewal pathways in leukaemia with the aim to further characterize the underlying molecular mechanisms and identify potential therapeutic targets for effective cancer therapies. Candidates are expected to have a strong background and relevant publications in areas of normal/malignant stem cell biology, epigenetics and/or proteomics.
Transcriptional deregulation is a key component in molecular pathogenesis of human cancer. In acute myeloid leukaemia (AML) where leukaemic stem cells (LSCs) have been functionally identified, the most prevalent chimeric leukaemia associated transcription factors (LATFs) arise from mutations of the retinoic acid receptor (RAR?), the core-binding factors (either of its two subunits AML1 or CBF?) and the mixed lineage leukaemia protein (MLL) (So and Cleary, 2004), which are critical for generation and/or maintenance of normal hematopoietic stem cells (HSCs). To gain further insights into the underlying transformation mechanisms, we have molecularly dissected and functionally validated the transcriptional complexes associated with some of the most common LATFs. We demonstrated that 1) aberrant self-association is a prevalent mechanism for oncogenic activation of LATFs including RAR?, AML1 and MLL fusions (Kwok et al., 2006; So and Cleary, 2004); 2) recruitment of DNA binding cofactor, RXR is an essential component and a potential therapeutic target for RAR?-mediated transformation in acute leukaemia, in particularly those are resistant to the current ATRA therapy (Zeisig et al., 2007); 3) protein arginine methyltransferase 1 (PRMT1) is a novel and essential epigenetic component for an oncogenic MLL fusion complex, which also provided the first evidence linking PRMTs to human cancer (Cheung et al., 2007). With the emerging functions of various histone modification enzymes in human leukaemia, we propose that epigenetic therapies may represent an alternative and promising avenue for targeting LATFs in LSCs (Zeisig et al., 2008). In addition, we are also interested in dissecting the pathways such as Bmi-1 and wnt/b-catenin pathways required for development of LSCs (Smith et al., 2011; Yeung et al., 2010).
The purpose of this new post is to develop and expedite projects aimed at dissecting the epigenetic regulation during the development of normal and leukemia stem cells. The successful candidate will learn and apply cutting edge techniques to perform global epigenetic analyses on normal and leukemic stem cells derived from various conditional genetic inactivation models using small cell number ChIP-seq approaches (Shankaranarayanan et al., 2012; Shankaranarayanan et al., 2011). Strong focuses will be the crosstalk between PcG and TrxG proteins in normal haematpoietic stem cells and leukaemia development (Zeisig et al., 2011). Details about the lab can be found at www.ericso.org
Cheung N, Chan LC, Thompson A, Cleary ML, So CW (2007). Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol 9: 1208-15.
Kwok C, Zeisig BB, Dong S, So CW (2006). Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells. Cancer Cell 9: 95-108.
Shankaranarayanan P, Mendoza-Parra MA, van Gool W, Trindade LM, Gronemeyer H (2012). Single-tube linear DNA amplification for genome-wide studies using a few thousand cells. Nat Protoc 7: 328-38.
Shankaranarayanan P, Mendoza-Parra MA, Walia M, Wang L, Li N, Trindade LM et al (2011). Single-tube linear DNA amplification (LinDA) for robust ChIP-seq. Nat Methods 8: 565-7.
Smith LL, Yeung J, Zeisig BB, Popov N, Huijbers I, Barnes J et al (2011). Functional crosstalk between Bmi1 and MLL/Hoxa9 axis in establishment of normal hematopoietic and leukemic stem cells. Cell Stem Cell 8: 649-62.
So CW, Cleary ML (2004). Dimerization: a versatile switch for oncogenesis. Blood 104: 919-922.
Yeung J, Esposito MT, Gandillet A, Zeisig BB, Griessinger E, Bonnet D et al (2010). ?-catenin mediates the establishment and drug resistance of MLL leukemic stem cells. Cancer Cell 18: 606-618.
Zeisig BB, Arteaga MF, Thirant C, So CW (2011). Collaboration between PcG Proteins and MLL Fusions in Leukemogenesis: An Emerging Paradigm. Cancer Cell 20: 551-3.
Zeisig BB, Cheung N, Yeung J, So CW (2008). Reconstructing the disease model and epigenetic networks for MLL-AF4 leukemia. Cancer Cell 14: 345-7.
Zeisig BB, Kwok C, Zelent A, Shankaranarayanan P, Gronemeyer H, Dong S et al (2007). Recruitment of RXR by Homotetrameric RARalpha Fusion Proteins Is Essential for Transformation. Cancer Cell 12: 36-51.
|Qualification||PhD with strong background/experiences in epigenetic study|
|How to Apply||Please send your cover letter and CV directly to Prof. Eric So (email@example.com)|
|Application deadline||5 Nov 2012|
|Supervisor/ Principal Investigator||Prof. CW Eric So|
Prof. CW Eric So
Contact Email: firstname.lastname@example.org
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