A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network

Unnikrishnan, A; Guan, YF; Huang, Y; Beck, D; Thoms, JAI; Peirs, S; Knezevic, K; Ma, S; De Walle, IV; De Jong, IDE; Ali, Z; Zhong, L; Raftery, MJ; Taghon, T; Larsson, J; MacKenzie, KL; Van Vlierberghe, P; Wong, JWH; Pimanda, JE

A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network

Unnikrishnan, A Guan, YF Huang, Y

Beck, D Thoms, JAI Peirs, S Knezevic, K Ma, S De Walle, IV De Jong, IDE Ali, Z Zhong, L Raftery, MJ Taghon, T Larsson, J MacKenzie, KL Van Vlierberghe, P Wong, JWH Pimanda, JE

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Publication Type:: Journal Article
Citation:: Nucleic Acids Research, 2016, 44 (22), pp. 10644 - 10661
Issue Date:: 2016-12-01

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Field	Value	Language
dc.contributor.author	Unnikrishnan, A	en_US
dc.contributor.author	Guan, YF	en_US
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Thoms, JAI	en_US
dc.contributor.author	Peirs, S	en_US
dc.contributor.author	Knezevic, K	en_US
dc.contributor.author	Ma, S	en_US
dc.contributor.author	De Walle, IV	en_US
dc.contributor.author	De Jong, IDE	en_US
dc.contributor.author	Ali, Z	en_US
dc.contributor.author	Zhong, L	en_US
dc.contributor.author	Raftery, MJ	en_US
dc.contributor.author	Taghon, T	en_US
dc.contributor.author	Larsson, J	en_US
dc.contributor.author	MacKenzie, KL	en_US
dc.contributor.author	Van Vlierberghe, P	en_US
dc.contributor.author	Wong, JWH	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.date.available	2016-09-02	en_US
dc.date.issued	2016-12-01	en_US
dc.identifier.citation	Nucleic Acids Research, 2016, 44 (22), pp. 10644 - 10661	en_US
dc.identifier.issn	0305-1048	en_US
dc.identifier.uri	http://hdl.handle.net/10453/94507
dc.description.abstract	© The Author(s) 2016. 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-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show 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.	en_US
dc.relation.ispartof	Nucleic Acids Research	en_US
dc.relation.isbasedon	10.1093/nar/gkw804	en_US
dc.subject.classification	Developmental Biology	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Proteome	en_US
dc.subject.mesh	Repressor Proteins	en_US
dc.subject.mesh	Prognosis	en_US
dc.subject.mesh	Proportional Hazards Models	en_US
dc.subject.mesh	Proteomics	en_US
dc.subject.mesh	Transcription, Genetic	en_US
dc.subject.mesh	Gene Expression Regulation, Leukemic	en_US
dc.subject.mesh	Binding Sites	en_US
dc.subject.mesh	Base Sequence	en_US
dc.subject.mesh	Consensus Sequence	en_US
dc.subject.mesh	Protein Binding	en_US
dc.subject.mesh	Proto-Oncogene Proteins c-ets	en_US
dc.subject.mesh	Ikaros Transcription Factor	en_US
dc.subject.mesh	Gene Regulatory Networks	en_US
dc.subject.mesh	Leukemia, Myeloid, Acute	en_US
dc.subject.mesh	Enhancer Elements, Genetic	en_US
dc.subject.mesh	Kaplan-Meier Estimate	en_US
dc.subject.mesh	Transcriptional Regulator ERG	en_US
dc.title	A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network	en_US
dc.type	Journal Article
utslib.citation.volume	22	en_US
utslib.citation.volume	44	en_US
utslib.for	080301 Bioinformatics Software	en_US
utslib.for	05 Environmental Sciences	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	08 Information and Computing Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Software
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.issue	22	en_US
pubs.publication-status	Published	en_US
pubs.volume	44	en_US

Abstract:

© The Author(s) 2016. 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-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/94507