Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb

Zhao, L., Glazov, E. A., Pattabiraman, D. R., Al-Owaidi, F., Zhang, P., Brown, Matthew. A., Leo, P. J., & Gonda, T. J. (2011) Integrated genome-wide chromatin occupancy and expression analyses identify key myeloid pro-differentiation transcription factors repressed by Myb. Nucleic Acids Research, 39(11), pp. 4664-4679.

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Abstract

To gain insight into the mechanisms by which the Myb transcription factor controls normal hematopoiesis and particularly, how it contributes to leukemogenesis, we mapped the genome-wide occupancy of Myb by chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-Seq) in ERMYB myeloid progenitor cells. By integrating the genome occupancy data with whole genome expression profiling data, we identified a Myb-regulated transcriptional program. Gene signatures for leukemia stem cells, normal hematopoietic stem/progenitor cells and myeloid development were overrepresented in 2368 Myb regulated genes. Of these, Myb bound directly near or within 793 genes. Myb directly activates some genes known critical in maintaining hematopoietic stem cells, such as Gfi1 and Cited2. Importantly, we also show that, despite being usually considered as a transactivator, Myb also functions to repress approximately half of its direct targets, including several key regulators of myeloid differentiation, such as Sfpi1 (also known as Pu.1), Runx1, Junb and Cebpb. Furthermore, our results demonstrate that interaction with p300, an established coactivator for Myb, is unexpectedly required for Myb-mediated transcriptional repression. We propose that the repression of the above mentioned key pro-differentiation factors may contribute essentially to Myb's ability to suppress differentiation and promote self-renewal, thus maintaining progenitor cells in an undifferentiated state and promoting leukemic transformation. © 2011 The Author(s).

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ID Code: 89354
Item Type: Journal Article
Refereed: No
Additional Information: Cited By :24
Export Date: 21 September 2015
CODEN: NARHA
Correspondence Address: Gonda, T. J.; University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia; email: t.gonda@uq.edu.au
Keywords: protein Myb, protein p300, transcription factor, transcription factor Cebpb, transcription factor Cited2, transcription factor Gfi1, transcription factor JunB, transcription factor PU 1, transcription factor RUNX1, unclassified drug, animal cell, article, cancer stem cell, cell differentiation, cell renewal, chromatin immunoprecipitation, controlled study, gene activation, gene control, gene expression profiling, gene mapping, gene sequence, hematopoiesis, hematopoietic stem cell, leukemia cell, leukemogenesis, mouse, myeloid progenitor cell, nonhuman, priority journal, protein function, protein protein interaction, transcription regulation, Animals, Binding Sites, Cells, Cultured, Chromatin, Gene Expression Regulation, Gene Regulatory Networks, Genomics, Histones, Leukemia, Mice, Mice, Inbred C57BL, Myeloid Progenitor Cells, Myelopoiesis, p300-CBP Transcription Factors, Proto-Oncogene Proteins c-myb, Repressor Proteins, Transcription Factors, Transcription, Genetic
DOI: 10.1093/nar/gkr024
ISSN: 0305-1048
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 21 Oct 2015 02:44
Last Modified: 19 Aug 2016 03:00

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