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You searched for +publisher:"University of New South Wales" +contributor:("Unnikrishnan, Ashwin, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW"). One record found.

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University of New South Wales

1. Guan, Yi Fang. Proteomics based approaches to identify DNA binding transcriptional regulators and phosphoproteins of ERG.

Degree: Clinical School - Prince of Wales Hospital, 2017, University of New South Wales

Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-cell acute lymphoblastic leukaemia (T- ALL) and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remain poorly understood. In order to discover transcriptional regulators of ERG, I employed a quantitative mass spectrometry (MS)-based method to identify factors binding the ERG +85 stem cell enhancer region in MOLT-4 and KG-1 cells. Using this approach, I identified a number of known transcription factors (TF) bound to the ERG +85 enhancer in leukaemic cells along with previously unknown binders, ETV6 and IKZF1. I confirmed that ETV6 and IKZF1 were also bound in vivo at the ERG +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells (HSPCs). Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators of ERG and a number of genes regulated by a densely interconnected network of the heptad TF. Furthermore, I showed that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.Protein phosphorylation is known to regulate the transcriptional activity of genes. Aberrant protein phosphorylation can lead to numerous haematological malignancies, but few studies have focused on phosphorylations of DNA bound TF at regulatory DNA. By adapting the reverseChIP method I develop an approach to identify and quantify of site-specific phosphorylation if TF on DNA in vitro using MOLT-4 and KG-1 cells. I have identified phosphorylated DNA bound TFs and 28 novel phosphorylation sites that are uniquely enriched at the ERG+85 enhancer under a leukaemia context. Oncoprotein ETS1 was identified as exhibiting changes in phosphorylation when bound to DNA compared to the nuclear input, this finding was also validated by western blot.This work significantly expands existing knowledge of the regulation of ERG over-expression driven by the ERG+85 enhancer in leukaemic and HSPCs cells. In addition, both reverseChIP methods can be utilised to study other regulatory regions of interest. Advisors/Committee Members: Pimanda , John Eshantha Manil Obeyesekere, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW, Wong, Jason Wing Hon, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW, Unnikrishnan, Ashwin, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW.

Subjects/Keywords: transcriptional network; ERG; hematopoietic stem cells

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APA (6th Edition):

Guan, Y. F. (2017). Proteomics based approaches to identify DNA binding transcriptional regulators and phosphoproteins of ERG. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/57197 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42784/SOURCE02?view=true

Chicago Manual of Style (16th Edition):

Guan, Yi Fang. “Proteomics based approaches to identify DNA binding transcriptional regulators and phosphoproteins of ERG.” 2017. Doctoral Dissertation, University of New South Wales. Accessed June 04, 2020. http://handle.unsw.edu.au/1959.4/57197 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42784/SOURCE02?view=true.

MLA Handbook (7th Edition):

Guan, Yi Fang. “Proteomics based approaches to identify DNA binding transcriptional regulators and phosphoproteins of ERG.” 2017. Web. 04 Jun 2020.

Vancouver:

Guan YF. Proteomics based approaches to identify DNA binding transcriptional regulators and phosphoproteins of ERG. [Internet] [Doctoral dissertation]. University of New South Wales; 2017. [cited 2020 Jun 04]. Available from: http://handle.unsw.edu.au/1959.4/57197 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42784/SOURCE02?view=true.

Council of Science Editors:

Guan YF. Proteomics based approaches to identify DNA binding transcriptional regulators and phosphoproteins of ERG. [Doctoral Dissertation]. University of New South Wales; 2017. Available from: http://handle.unsw.edu.au/1959.4/57197 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:42784/SOURCE02?view=true

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